Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:3][CH3:4])=[O:2].[C:14]([O:17][CH2:18][C:19](Cl)=[O:20])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:18][C:19]([C:13]1[N:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])=[O:20])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COC(=O)c1cc2ccccn2c1
Product: COC(=O)c1cc2ccccn2c1C(=O)COC(C)=O

Procedure:
Following the procedure of Example 3, reaction of 2-carbomethoxyindolizine with acetoxyacetyl chloride gave 3-acetyloxyacetyl-2-carbomethoxyindolizine (IX). Reaction of IX with 1.5 equiv of anhydrous hydrazine in dry ethanol gave 4-hydroxymethylpyridazino[4,5-b]indolizin-1-one which upon refluxing with excess POCl3 gave 1-chloro-4-chloromethylpyridazino[4,5-b]indolizine (X). Compound X (1.0 g, 4.0 mmol) was combined with excess N,N-diethylaminopropylamine (2.68 mL, 17 mmoL) in N-methylpyrrolidinone (2 mL) containing TEA (0.74 mL, 1.2 equiv.) and 1.2 equiv. of ammonium chloride (vigorous initial reaction with gas evolution). When the reaction subsided the stirred reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the volatiles were removed by vacuum distillation. The residue was dissolved in methylene chloride and extracted with water (3 times), dried (MgSO4), and the solvent evaporated. The residue was purified by flash column chromatography on silica gel eluting with 20% methanol in methylene chloride containg 2% ammonium hydroxide. The isolated free base was converted to the tetra hydrochloride salt using ethereal HCl in ether m.p. 120°-123° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:14][C:15]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)OC1CCCC1
Reaction time: 2.5 h

Procedure:
Cyclopentanol (0.431 mL, 4.75 mmol, 17.4 equiv) was dissolved in dry CH2Cl2 (25 mL). Triethylamine (0.662 mL, 4.75 mmol, 17.4 equiv) and triphosgene (0.507 g, 1.71 mmol, 6.26 equiv) were added sequentially. The reaction solution was stirred 2.5 hours to provide a stock solution of cyclopentyl chloroformate (0.19 M). A portion of this solution (2.87 mL, 0.545 mmol, 2 equiv) was added to a solution of crude ethyl-3-[H2N-L-ValΨ[COCH2]-L-(p-F)Phe-L-(Tr-Gln)]-E-propenoate•HCl(from above) and 4-methylmorpholine (0.120 mL, 1.09 mmol, 4 equiv) in dry CH2Cl2 (4 mL). The reaction mixture was stirred for 1.75 hours, then poured into water (30 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic phases were dried over Na2SO4, concentrated, and the residue was chromatographed on silica gel (gradient elution 40-50% EtOAc in hexanes) to afford ethyl-3-[CyPentylOCO-L-ValΨ[COCH2]-L-(p-F)Phe-L-(Tr-Gln)]-E-propenoate (0.077 g, 35%) as a colorless glass: 1H NMR (CDCl3) δ 0.68 (d, 3H, J=6.8), 0.93 (d, 3H, J=6.8), 1.29 (t, 3H, J=7.2), 1.50-1.86 (m, 10H), 1.93-2.04 (m, 2H), 2.52 (d, 1H, J=15.9), 2.64 (dd, 11H, J=12.1, 5.6), 2.73-2.90 (m, 2H), 2.29 (dd, 1H, J=17.0, 9.8), 4.10-4.22 (m, 3H), 4.40-4.51 (m, 1H), 4.92 (d, 1H, J=8.1), 4.95-5.03 (m, 1H), 5.38 (d, 1H, J=15.9), 6.06 (d, 1H, J=8.4), 6.60 (dd, 1H, J=15.9, 4.8), 6.92-7.00 (m, 2H 7.04-7.11 (m, 211), 7.16-7.32 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Reactant: Oc1cncc(Cl)c1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Cl)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 5-chloro-3-pyridinol (20.0 g, 0.154 mol, Aldrich) and KOH (13.0 g, 0.232 mol) in 300 mL of water at 0° C. was added p-nitrobenzenediazonium tetrafluoroborate (36.6 g, 0.154 mol, Aldrich). After 1 hour, 50 mL of glacial acetic acid was added, and the bright red precipitate was filtered and air-dried. Chromatography (silica gel; CH2Cl2/MeOH, 95:5-90:10) afforded the title compound as a bright red solid (28.8 g, 67%): 1H NMR (DMSO-d6, 300 MHz) δ7.14 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 8.00 (m, 2H), 8.39 (m, 2H); MS (CI/NH3) m/z: 279, 281 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2C=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:31]=[CH:32][N:33]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][OH:30])[CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrC1N2N=CN=C2C(NC2C=NC(N3CCN(C(C)C)CC3)=CC=2)=[N:37]C=1>>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:37]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:31]=[CH:32][N:33]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][OH:30])[CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccnc(CO)c4)n4ncnc34)cc2)CC1
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccnc(CO)c4)n4ncnc34)cn2)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 83, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]amine in Step 4. LCMS: Rt=0.71 min (95%), m/z (ESI) 446 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Temperature: 0 °C

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (0.25 g, 0.80 mmol) was dissolved in dichloromethane (3.2 mL) and triethylamine (0.34 mL, 2.4 mmol) was added. The reaction was cooled to 0° C. and methanesulfonyl chloride (0.069 mL, 0.88 mmol) was added and the reaction was allowed to warm to room temperature. The solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCOC(=O)CCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (300 mg, 0.51 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-ethyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]=[O:29])[CH:9]=1.[CH2:40]1COCC1.C[Mg]Br.CCOCC>O>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:29])[CH3:40])[CH:9]=1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (11.0 g, 19.4 mmol) in anhydrous THF (200 mL, 2 mol) under nitrogen at 0° C. was added 3M methylmagnesium bromide in ether (9.69 mL, 29.0 mmol) dropwise. After 1 hour the reaction was complete by HPLC. Water (10 mL) was added over a 15 minute period to quench the reaction. Removed the flask from the ice bath and concentrated in vacuo. Dissolved the remaining residue in ethyl acetate, washed three times with water and then twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified the remaining crude material by flash chromatography (5-40% EtOAc/hex) to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.8 g; 60% yield) as a yellow solid. HPLC: 7.54 min (Method C). LCMS: ESI+ m/z of 584 (M+H)
Reaction SMILES: C(O)C(O)C.[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16].SC(O)C.C(OOC(C)(C)C)(=O)C>>[CH:6]([CH2:17][C:15](=[CH2:16])[C:14]([OH:19])=[O:18])=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)C(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(=O)OOC(C)(C)C
Agent: CC(O)S
Solvent: CC(O)CO
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 150 °C

Procedure:
A 1-liter, four-necked, round bottomed flask equipped with a mechanical stirrer, two addition funnels, a distillation head with a variable takeoff, a thermometer, a nitrogen inlet, and a heating mantle atop a thermosensor-controlled pot lifter is charged with 300 g of propylene glycol. This heel charge is heated to 150° C. under nitrogen. The monomer charge (135 g styrene, 165 g methacrylic acid, and 3 g mercaptoethanol) is gradually charged over 5 hours. Simultaneously, the initiator solution (9.0 g of 70% t-butyl peracetate) is added over the same period. After completion of the feeds, an additional 0.9 g of t-butyl peracetate solution is added and the batch held at150° C. for another hour.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[O:20]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: c1ccc(Oc2cncc(N3CCNCC3)n2)cc1
Temperature: 165 °C
Reaction time: 4.5 h

Procedure:
A mixture of the product obtained in example 13, step 2 (1.97 g, 9.92 mmol), phenol (2.43 g, 25.8 mmol), CuO (1.0 g, 12.6 mmol), and K2CO3 (1.43 g, 10.3 mmol) in dioxane (2 mL) was stirred for 4.5 h at 165° C. in a sealed pyrex tube. The reaction mixture was diluted with CHCl3 and filtered through a pad of Celite. The pad was washed with several portions of CHCl3/MeOH (95:5). Solvent removal in vacuo furnished a dark brown oil which was purified by column chromatography on silica gel (14×5 cm) using CHCl3/MeOH (95:5, followed by 90:10) as eluent. The brown oil (1.66 g) was subjected to repeated column chromatography, first on silica gel (18×4 cm) using CHCl3/MeOH (9:1) as eluent and finally on alumina (4×5 cm) using ether/MeOH (95:5) as eluent. This furnished 1.37 g (54%) of the title compound as a light beige oil. HRMS m/z calcd for C14H16N4O (M)30 256.1324, found 256.1321. Anal. (C14H16N4O) C, H, N.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[NH:10])[CH:6]=[CH:5][CH:4]=1.C[O-].[Na+]>CO.COC(OC)CC(=O)C>[Br:2][C:3]1[N:8]=[C:7]([C:9]2[N:11]=[C:5]([CH3:6])[CH:4]=[CH:3][N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1cccc(Br)n1
Agent: COC(CC(C)=O)OC
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: Cc1ccnc(-c2cccc(Br)n2)n1
Yield: 168.3 %

Procedure:
To a mixture of 6-bromo-2-picoline amidine hydrochloride (10 g) and methanol (200 ml) were added 28% sodium methoxide solution in methanol (10.6 g) and 1,1-dimethoxy-3-butanone (6.1 g). The mixture was heated under refluxing for an hour, and then concentrated under reduced pressure. Water (100 ml) and ethylacetate (200 ml) were added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was washed with n-hexane to obtain 2-(6-bromo-2-pyridinyl)-4-methylpyrimidine (8.9 g, yield 84%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>C(O)C.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>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1
Reactant: COc1ccccc1S
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Yield: 68.8 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.6 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert-butoxide (11.0 g), 2-methoxybenzenethiol (5.3 g) and tetrakis(triphenylphosphine)palladium(0) (0.45 g) were added and the mixture heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed first on silica using 1:1 hexane:dichloromethane as the eluent and then on silica using 24:1 hexane:ethyl acetate as the eluent to yield 6-(2-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (8.12 g) as an oil.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=S)[S-:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].C([NH+](CC)CC)C.C(N(CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(NC(=S)[S-])cc2)CC1
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
428 mg of triethylammonium p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyldithiocarbamate were dissolved in 4 ml of chloroform and the solution was treated under argon with 284 μl of triethylamine. The mixture was subsequently cooled to 0° C. and treated dropwide with 194 μl of ethyl chloroformate. The mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 1 hour. The reaction mixture was subsequently partitioned between 100 ml of diethyl ether and 100 ml of water. The aqueous phase was back-extracted twice with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the oily residue (450 mg) on 35 g of silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 234 mg (51%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyl isothiocyanate as colourless crystals. By recrystallization from 10 ml of methanol at 0° C. there were obtained 119 mg of p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyl isothiocyanate of melting point (C--I) 61.2° C. and cl.p. (N--I) 49.0° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:4]=[N:3]1.Cl[C:17]1[N:25]=[C:24]2[C:20]([N:21]=[C:22]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]3)[N:23]2[CH3:26])=[C:19]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:18]=1>>[CH3:26][N:23]1[C:22]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]2)=[N:21][C:20]2[C:24]1=[N:25][C:17]([N:11]1[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)=[N:18][C:19]=2[N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cn1nccc1-c1nc2ccccc2[nH]1
Product: Cn1nccc1-c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 319. LCMS m/z: 571.3 (MH+)
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]([CH:21]3[CH2:23][CH2:22]3)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:21]1([CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:5]3[S:6][C:2]([C:36]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:35]=4[F:34])=[C:3]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[N:4]=3)[CH:10]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:23][CH2:22]1
Reactant: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(Br)s2)c1)C1CC1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(-c3cc(OC)ccc3F)s2)c1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To methyl 3-(3-((5-bromo-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methoxy)phenyl)-3-cyclopropylpropanoate (115 mg) in toluene (10 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (108 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (26 mg), tris(dibenzylideneacetone)dipalladium(0) (20 mg) and 2.0 M aqueous sodium carbonate solution (0.32 mL), and the mixture was stirred at 100° C. for 1 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (120 mg) as orange crystals.
Reaction SMILES: O[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2[nH]1
Product: Clc1nc2ccccc2[nH]1
Reaction time: 18 h

Procedure:
A mixture of 2-hydroxybenzimidazole (300 g, 2.42 mol) and phosphorus oxychloride (1000 g) was heated at reflux temperature for 1 h to obtain a solution. Gaseous HCl was bubbled into the refluxing solution for 4 h and the solution then concentrated on a rotary evaporator. The residue was added to a mixture of aqueous potassium carbonate and methylene chloride and stirred for 18 h. The resulting mixture consisted of 2 liquid layers and a solid. The solid was collected and recrystallized from ethyl acetate and methanol.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.O1CCCC1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(Cl)cc3Cl)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2Cl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.7 %

Procedure:
7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(2,4-dichlorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.) and tetrahydrofuran (30 ml.) were added to a solution of sodium acetate (4.6 g.) in water (100 ml.), and then the mixture was stirred at room temperature for 5 days. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was separated. Ethyl acetate and tetrahydrofuran were added to the aqueous solution and adjusted to pH 6.2 with 10% hydrochloric acid. The aqueous layer was separated and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.). m.p. 167° to 193° C. (dec.).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8](F)=[C:9]([F:12])[C:10]=1[F:11])[OH:5].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:3][C:4]([C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])([C:6]1[S:7][C:8]([Br:1])=[C:9]([F:12])[C:10]=1[F:11])[OH:5]
Reactant: BrBr
Reactant: OC(F)(c1sc(F)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OC(F)(c1sc(Br)c(F)c1F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (0.698 g) was added to a solution of 1 (1.80 g, 4.16 mmol) in CH2Cl2 (15 mL). After stirring overnight at room temperature, the mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo (1.90 g, 89%).