Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1.[F:38][CH2:39]CC#C.FCC#C>>[F:38][CH2:39][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1
Reactant: C#CCCF
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared according for the procedure for compound 6, with the exception that 4-fluorobut-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]7, 4-[18F]fluorobut-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].BrN1C(=O)CCC1=O.BrCC1C=CC=C(C)[C:24]=1[C:25]([O:27]C)=[O:26].C([O-])(=O)C.[Na+].[Cl-].[NH4+]>ClC(Cl)C.CS(C)=O.[W].N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC.C(OCC)(=O)C>[C:25]([O:27][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[CH3:24]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: COC(=O)c1c(C)cccc1CBr
Agent: [W]
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(C)cccc1COC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of methyl 2,6-dimethylbenzoate (described in J. Am. Chem. Soc., 99, 6405 (1977); 23.4 g, 143 mmol) in dichloroethane (200 ml) were added N-bromosuccinimide (25.46 g, 143 mmol) and α,α′-azobisisobutyronitrile (234.8 mg, 1.43 mmol), and the mixture was irradiated with visible light (tungsten lamp, 375 W) for 1 hour. After cooling the reaction mixture, the precipitated material was filtered off, and the solvent was distilled off under reduced pressure. The obtained oily residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:10) to give an oily mixture containing ca. 50% methyl 2-(bromomethyl)-6-methylbenzoate. The mixture was dissolved in dimethyl sulfoxide (150 ml), and sodium acetate (16.4 g, 0.2 mol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours, then a saturated aqueous solution of ammonium chloride was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:10˜1:3) to give methyl 2-(acetoxymethyl)-6-methylbenzoate (8.09 g, more than 80% content) as a colorless oil. The obtained methyl 2-(acetoxymethyl)-6-methylbenzoate was used for the following reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]=[CH:13][C:14]([OH:16])=O)=[O:11])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].C1(C)C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.Cl>CCOC(C)=O.[Br-].[Zn+2].[Br-].CCCCCCC>[O:16]=[C:14]1[CH:13]=[CH:12][C:10](=[O:11])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: N#Cc1ccc(NC(=O)C=CC(=O)O)cc1C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
Compound 516A (17.42 mmoles, 5.000 g) was added to the reaction flask followed by the addition of zinc bromide (17.58 mmoles, 3.960 g) and then toluene (50.00 mL, 43.25 g) was added to the mixture. The resulting suspension was stirred for 20 min. Hexamethyldisilazane (26.35 mmoles, 5.560 mL, 4.253 g) was added to this suspension which was then heated to 60° C. for 4.5 h. The reaction mixture was diluted with EtOAc (25 mL) and then poured into a 1N HCl solution (30 mL) at 25° C. The organic phase was collected and the aqueous phase was extracted with EtOAc (15 mL). The organic phase was isolated, combined with the earlier organic phase and washed consecutively with saturated NaHCO3 (15 mL), a mixture of 1:1 water:brine solution (15 mL) and brine (15 mL). The resulting solution was dried over MgSO4, filtered and concentrated in vacuo to a 50 mL suspension. Heptane (125 mL) was added dropwise to this suspension with agitation. The resulting thicker suspension was filtered and washed with a mixture of 2:1 heptane:toluene (15 mL) and then heptane (15 mL) to give 4 g (85% yield) of compound 516B. HPLC: 100% at 2.11 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]([NH:9][CH2:10][CH2:11][F:12])=[N:8][C:4]=2[CH:3]=1.[CH3:22][C:23]([O:26][C:27]([N:29]1[CH2:35][C:34]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=2[O:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.ClC(OCC(C)C)=O>C(OCC)(=O)C.O.O1CCOCC1>[F:12][CH2:11][CH2:10][NH:9][C:7]1[N:6]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:5]2[CH:20]=[CH:21][C:2]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH2:31][CH2:30][N:29]([C:27]([O:26][C:23]([CH3:24])([CH3:22])[CH3:25])=[O:28])[CH2:35][C:34]=4[CH:36]=3)=[CH:3][C:4]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: CC(C)COC(=O)n1c(NCCF)nc2cc(Br)ccc21
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)COC(=O)n1c(NCCF)nc2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)ccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Isobutyl 5-bromo-2-(2-fluoroethylamino)-1H-benzo[d]imidazole-1-carboxylate (55 mg, 0.15 mmol) and (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (50 mg, 0.17 mmol) were taken into dioxane (1 mL) and water (0.2 mL) followed by addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (8.5 mg) and DIPEA (0.11 mL, 0.6 mmol) and the mixture was heated to 85° C. for 12 h. The mixture was then cooled and diluted with ethyl acetate then dried over anhydrous sodium sulfate and filtered through a plug of silica gel with an ethyl acetate wash. The organic solution was then concentrated to an oil. The residue was taken into THF (2 mL) followed by sequential addition of DIPEA (0.05 mL, 0.29 mmol) and isobutyl chloroformate (0.01 mL, 0.08 mmol) then the mixture was stirred for 30 minutes. The mixture was concentrated and the residue purified by silica gel chromatography (1.5:1 hexanes:ethyl acetate) to give 1,1-dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (59.4 mg, 75% yield) as a colorless amorphous residue. MS (EI) for C28H35FN4O5: 528 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH:11]=1)[NH2:10].[O-:20][C:21]#[N:22].[Na+]>C(O)(=O)C.O.Cl>[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([NH:10][C:21]([NH2:22])=[O:20])[CH:11]=1
Reactant: N#C[O-]
Reactant: NCCc1ccc(OCc2ccccc2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NCCc1ccc(OCc2ccccc2)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
2.4 g of 5-(2-aminoethyl)-2-benzyloxyaniline, hydrochloride, is dissolved in a mixture of 20 ml of acetic acid, 5 ml of water and 0.5 ml of 2N hydrochloric acid. A solution of 0.72 g of sodium cyanate in 5 ml of water is added and the mixture is stirred for one hour at room temperature. Thereafter, the mixture is diluted with 100 ml of water, the product is extracted by shaking with methylene chloride and recrystallized from isopropanol, thus obtaining 0.56 g of N-[5-(2-aminoethyl)-2-benzyloxyphenyl]urea, mp 176°-180° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Br:31]C1C=C2C(=CC=1)NC=C2CC(O)=O>>[Br:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[NH:8][CH:7]=[C:6]2[CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)=[O:13]
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-1H-indol-3-yl)acetic acid in step 20 (A), the title compound was prepared. MS (ESI) (M+H)+=509.84/511.92/513.90 1H-NMR (500 MHz, CD3OD) δ 7.73 (d, J=1.53 Hz, 1 H), 7.46 (s, 2 H), 7.29-7.40 (m, 2 H), 7.26 (d, J=1.83 Hz, 1 H), 4.54 (s, 2 H), 3.96 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[Br-].[O:16]1CCO[CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:21][CH:17]=[O:16])=[CH:9][CH:8]=1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=CC=Cc1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 4-(2-pyrimidinyl)-benzaldehyde (1.83 g, 9.94 mmol, prepared as described in WO 9828264), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and air-dried. Recrystallization from 2-propanol provided 1.20 g (57%) of the title compound as a light yellow solid. MS 211 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[O:11]=[C:12]1[CH2:16][CH2:15][O:14][CH2:13]1>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:12]2([OH:11])[CH2:16][CH2:15][O:14][CH2:13]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCOC1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCOC1
Temperature: 85 °C
Reaction time: 72 h
Yield: 9.8 %

Procedure:
to a solution of 1-bromo-3,5-difluoro-benzene (4.00 g, 20.7 mmol) in tetrahydrofuran (70 mL) under nitrogen was added magnesium (6.0 equiv., 124 mmol) and the solution was heated at 85° C. for three hours. The solution was cooled to rt and 3-oxotetrahydrofuran (1 equiv., 20.726 mmol) in THF (20 mL) was added via syringe. The mixture was stirred at rt for three days. The reaction was quenched with sat NaHCO3, extracted with EtOAc and washed with brine. Purification by CombiFlash (0 to 100% EtOAc in heptane) provided the title compound (405 mg, 9.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][S:9][C:8]2=[O:20])=[CH:4][CH:3]=1.[CH3:23][S:24][CH2:25][C:26](OCC)=[O:27].C(OCl)(C)(C)C.C(N(CC)CC)C.Cl.[OH-].[Na+]>CC#N.C1COCC1.C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH2:10][S:9][C:8](=[O:20])[N:7]([CH2:6][C:5]3[CH:21]=[C:22]4[C:2](=[CH:3][CH:4]=3)[NH:1][C:26](=[O:27])[CH:25]4[S:24][CH3:23])[N:12]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(CN2N=C(c3ccc(Cl)cc3)CSC2=O)cc1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2ccc(CN3N=C(c4ccc(Cl)cc4)CSC3=O)cc21
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step C (38.27 mmoles), in a mixture of CH3CN (115 ml) and THF (115 ml) at −60° C., ethyl (methylsulphanyl)acetate (45.92 mmoles) is added dropwise under a nitrogen atmosphere. tBuOCl (45.92 mmoles) is added dropwise to the reaction mixture over 20 minutes, keeping the temperature between −60° C. and −55° C. After stirring for 1 hour at −60° C., triethylamine (51.66 mmoles) is added dropwise. The reaction mixture is brought to ambient temperature. 240 ml of DCM and then aqueous 3M HCl solution (340 ml) are added. After stiffing for 12 hours at ambient temperature, the reaction mixture is made alkaline (pH 10-11) using 20% aqueous sodium hydroxide solution. After extraction with DCM, the organic phase is washed with saturated aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The product obtained is triturated in ethyl ether, filtered and dried in vacuo to yield the title product which is used directly in the next Step.
Reaction SMILES: C([Li])(C)(C)C.Br[C@@H:7]1[CH2:9][C@H:8]1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1.[F:18][C:19]([F:29])([F:28])[C:20](=[O:27])[C:21]#[C:22][Si](C)(C)C.Cl>C(OCC)C.O1CCCC1.O.CO>[Cl:17][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:9][CH:7]2[C:20]([OH:27])([C:21]#[CH:22])[C:19]([F:29])([F:28])[F:18])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: Clc1ccc([C@@H]2C[C@H]2Br)cc1Cl
Reactant: C[Si](C)(C)C#CC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: C#CC(O)(C1CC1c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: -100 °C
Reaction time: 1 h

Procedure:
t-Butyl-lithium (1.1 ml. of a 1.8 molar solution in diethyl ether) was added dropwise to a solution of trans-1-bromo-2-(3,4-dichlorophenyl)cyclopropane (0.53 g.) In a mixture of diethyl ether (18 ml.) and tetrahydrofuran (2 ml.) which was maintained at -100° C., and the mixture was stirred at that temperature for 1 hour. A solution of 1,1,1-trifluoro-4-trimethylsilylbut-3-yn-2-one (0.39 g.) in tetrahydrofuran (5 ml.) was added dropwise, the mixture was stirred at -100° C. for 2 hours and a mixture of methanol (1 ml.) and aqueous 2N-hydrochloric acid (1 ml.) was added. The mixture was allowed to warm up to laboratory temperature and was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. Tetra-n-butylammonium fluoride (0.16 g.) was added to a stirred solution of the residue in tetrahydrofuran (25 ml.) and the mixture was stirred at laboratory temperature for 4 hours, diluted with water (100 ml.) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using an 11:9 v/v mixture of petroleum ether (b.p. 60°-80° C.) and methylene chloride as eluant. There was thus obtained as an oil 2-[2-(3,4-dichlorophenyl)cyclopropyl]-1,1,1-trifluorobut-3-yn-2-ol.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CO.C(Cl)Cl>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([C:5]1[C:4]([O:28][CH3:29])=[CH:3][C:2]([C:33]3[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=3)=[C:7]([F:8])[CH:6]=1)=[N:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2cc(F)cc(F)c2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 30.5 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 88.75 mg, 0.197 mmol). (3,5-difluorophenyl)boronic acid (62.2 mg, 0.394 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.020 mg, 4.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (7.46 mg, 9.84 μmol), and potassium phosphate (125 mg, 0.590 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (895 μl) and water (89 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-4% MeOH/DCM, then with 4-10% MeOH/DCM) to give N-(1,3,4-thiadiazol-2-yl)-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonamide (31.54 mg, 0.060 mmol, 30.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.90 (dd, J=1.8, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.43-7.34 (m, 3H), 3.73 (s, 3H). m/z (ESI) 528.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cn1
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (130 mg, 0.44 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (98 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.66 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate: hexane (0-100%) to give the desired compound as an off-white powder (50 mg, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[CH2:11][C:12]#[N:13]>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]#[N:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC1
Reactant: N#CCCl
Product: COC(=O)C1(CC#N)CCCC1
Yield: 38 %

Procedure:
1-(Cyanomethyl)cyclopentane carboxylic acid methyl ester was prepared from cyclopentane carboxylic acid methyl ester and chloroacetonitrile using the procedure described in example 7 to give a 38% yield. HR MS (C9H13NO2): Obs mass, 167.0173. Calcd mass, 167.0146 (M+).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=[C:15]4[N:14]=[C:13]([CH3:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12.CO.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOCC.CCCCCC>[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O:26][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=[C:15]4[N:14]=[C:13]([CH3:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Agent: NN=C(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension comprising 30 g of 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylic acid, 170 ml of methanol and 510 ml of methylene chloride was added dropwise while stirring diphenyldiazomethane, which had been synthesized from 39.25 g of benzophenonehydrazone, 43.22 g of mercuric oxide (yellow) and 350 ml of n-hexane, in 50 ml of methylene chloride, and the mixture was stirred at room temperature overnight. After the reaction mixture was condensed and ether was added thereto to effect crystallization. The crystals were collected by filtration and dried, and the resulting powder was purified through silica gel column chromatography to obtain 31.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[NH:9][CH:10]=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N)=O.CN(C=O)C.O=P(Cl)(Cl)Cl.CCOC(C)=O.C(Cl)Cl>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=CNC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nccn2cnc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A solution of formamide N-[(3-chloro-pyrazin-2-yl)-(4-phenoxy-phenyl)-methyl]-formamide (1.85 g, 5.45 mmol) in CH3CN (50 mL) at 0° C. was added DMF (0.4 mL) and POCl3 (1.52 mL, 16.3 mmol). The mixture was allowed to warm to rt over 16 h. TLC (EtOAc/CH2Cl2, 1:1) showed no starting material. Reaction mixture was evaporated to remove solvents. To the residue was added aq. satd. NaHCO3 (100 mL) and extracted with EtOAc (3×50 mL). Organic layer was washed with water (30 mL) and dried (Na2SO4). Evaporation of solvent gave titled compound (1.62 g, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.13-7.21 (m, 5H), 7.29-7.31 (m, 3H), 7.60-7.64 (m, 2H), 7.68 (d, J=2.4 Hz, 1H), 8.30 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:20])[F:19])[C:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1)=[C:8]2[CH3:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Yield: 95.5 %

Procedure:
A solution of [8-chloro-2-difluoromethoxy-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.14 g), methanol (5.0 mL), saturated aqueous lithium hydroxide solution (0.5 mL) and water (0.4 mL) was stirred at room temperature for 35 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid 0.13 g.