Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:12]=3[C:13]([NH:27][C:28]3([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)[CH2:30][CH2:29]3)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)cc4)C3)CC2)cc1
Yield: 60 %

Procedure:
The title compound (D173) (80 mg) was prepared according to the experimental procedure described in Description 146 starting from 2-(3-(4-fluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D122) (90 mg, 0.252 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (57.51 mg, 0.252 mmol).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].C(N(CC)C(C)C)(C)C.[C:20]1([C:26]2[O:27][CH2:28][C:29](=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([C:26]2[N:30]=[C:29]([CH2:28][OH:27])[N:3]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=3)[N:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1cccnc1
Reactant: O=C1COC(c2ccccc2)=N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OCc1nc(-c2ccccc2)nn1-c1cccnc1

Procedure:
To a solution of 3-hydrazinylpyridine dihydrochloride (336 mg, 1.84 mmol) and N,N-diisopropylethylamine (476 mg, 644 μL, 3.69 mmol) in ethanol (7 mL) was added 2-phenyloxazol-4(5H)-one (300 mg, 1.68 mmol, example 55, step 1) and the reaction mixture was refluxed for 2 h. All volatiles were removed in vacuo, and the product was obtained after purification by flash chromatography (using silica gel and a methanol/ethyl acetate gradient) as light yellow solid (390 mg, 1.546 mmol, 92.3%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[C:20]([I:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:22][CH3:23])[N:14]=1.C(OCC)(=O)C>ClCCl>[NH2:12][C:13]1[C:20]([I:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([S:22]([CH3:23])=[O:9])[N:14]=1
Reactant: CSc1nc(N)c(I)cc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(N)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1.77 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.89 g (6.51 mmol) of 6-amino-5-iodo-2-(methylthio)nicotinonitrile in 60 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and evaporated to yield 1.5 g (75%) of 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 6-amino-5-iodo-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:22](=[O:24])[CH3:23])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid benzyl ester (600 mg, 2.39 mmol) in THF (10 mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 191 mg, 4.78 mmol). The mixture was stirred for 20 min at 0° C., acetyl chloride (339 μl, 4.78 mmol) was added and the resulting suspension was stirred at RT for 48 h. The solvent was concentrated and the residue poured in water and extracted twice with CH2Cl2. The Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 75:25) to give the desired product as a white solid. TLC, Rf (c-hexane/EtOAc 3:1)=0.38; MS (LC-MS): 294.1 [M+H]+, 316.0 [M+Na]+; tR (HPLC conditions a): 4.69 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[Na+].[Cl-].[C:14]1(C(O)(CCCC)CC)C=CC=C[CH:15]=1.CC1C=CC=CC=1C(O)(CC)C>C(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH2:14][CH3:15])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCCCC(O)(CC)c1ccccc1
Agent: CCC(C)(O)c1ccccc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(C)(O)c1ccc(OC)cc1
Yield: 85.2 %

Procedure:
The general procedure A was applied to 4-methoxyacetophenone on a 112 mg (0.73 mmol) scale, using 10 mol % of Compound B (40 mg). The crude product was purified by column chromatography on silica gel (hexanes/EtOAc: 8/2) to give 3 (112 mg, 85.2% yield, 94.0% ee) as an oil: [α]D 20=−13.32 (c 1.8, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.77 (dd, J=7.4, 7.4 Hz, 3H), 1.50 (s, 3H), 1.76-1.82 (m, 2H), 3.78 (s, 3H), 6.83-6.86 (m, 2H), 7.31-7.34 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 8.8, 29.9, 37.1, 55.6, 75.0, 113.7, 126.5, 140.3, 158.5 ppm; IR (NaCl) 3444, 2967, 1610, 1300, 1179 cm−1; MS (m/z relative intensity) 180 (M)+ (7), 165 (MCH3)+ (5), 163 (—OH)+ (49), 162 (M-H2O) (15); HMRS calcd for C11H15(—OH)+: 163.1122, found 163.1129.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[N:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41][NH2:42])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[N:19]=[C:20]([NH:42][CH2:41][CH2:40][CH2:39][NH:38][C:37](=[O:43])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(-c2ccncc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCNc1nc(-c2ccncc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 170 °C
Yield: 16.9 %

Procedure:
0.1 mmol N-cyclopropyl-4-[8-(methylsulfonyl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl]benzamide (intermediate example 9-2) (1 mL, 0.1 M in NMP), 0.2 mmol tert-butyl(3-aminopropyl)carbamate (0.4 mL, 0.5 M in NMP, 2 eq) and 0.3 mmol DIPEA (41 μL, 3 eq) were combined in a sealed vial and heated at 170° C. under microwave irradiation for 60 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 8.9 mg tert-butyl [3-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-8-yl}amino)propyl]carbamate (11%): 1H-NMR (300 MHz, d6-DMSO): δ=8.58 (2H, d), 8.54 (1H, d), 8.32 (1H, s), 8.02-7.93 (3H, m), 7.87-7.76 (4H, m), 6.83 (1H, tr), 3.58 (2H, m), 3.01 (2H, m), 2.86 (1H, m), 1.77 (2H, m), 1.32 (9H, s), 0.68 (2H, m), 0.55 (2H, m) ppm; UPLC-MS: RT=0.90 min; m/z (ES+) 528.6 [MH+]; required MW=527.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].N1(S(N)(=O)=O)CCC1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][CH2:17]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:36][S:33]([CH:30]1[CH2:32][CH2:31]1)(=[O:35])=[O:34])=[O:8]
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F
Agent: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5 and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.04 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H), 2.37-2.27 (m, 2H), 2.18-2.09 (m, 3H), 2.01-1.92 (m, 1H), 1.15-1.11 (m, 4H); MS (ES+) m/z 430.0, 432.0 (M+1); MS (ES−) m/z 428.1, 430.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[CH3:22].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[CH3:22])[NH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:19]
Reactant: CCOC(=O)C(=CNc1ccc(OC)c(C)c1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(C)c(OC)cc2c1=O
Temperature: 220 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Diethyl 2-[(4-methoxy-3-methyl-phenylamino)-methylene]-malonate (73.9 g) was dissolved in diphenyl ether (200 ml) to prepare a solution which was then stirred at 220° C. for 2 hr. The reaction solution was cooled to room temperature, hexane was then added to the reaction solution, and the precipitated crystal was collected by filtration to give ethyl 6-methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (25.5 g, yield 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][C:9]=1[NH2:27])[CH3:2].C(=O)C.CN1C(=O)[CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:22][C:21]4([CH3:24])[CH2:23][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]4)=[O:15])=[CH:10][C:9]=2[N:27]=[C:34]1[CH2:35][CH3:36])[CH3:2]
Reactant: CCOC(=O)CCNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1N
Reactant: CN1CCCC1=O
Agent: CC=O
Product: CCOC(=O)CCn1c(CC)nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of 3-[2-amino-4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenylamino]-propionic acid ethyl ester (250 mg, 0.645 mmol) in dry NMP (10 mL) at room temperature under an inert atmosphere of nitrogen was added approx. 200 mg of molecular sieve 4 Å followed by acetaldehyde (93 uL, 1.29 mmol). The mixture was stirred for 16 hrs at 50° C. The reaction was quenched by the addition of water (100 mL) followed by extraction with diethyl ether (3×100 mL). The combined organic phases were washed with brine (4×200 mL), dried (MgSO4), filtered, and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried in vacuo at 50° C. affording 104 mg (38%) of the title compound as brown oil. MS-ESI m/z 426; 1H NMR (400 MHz, CDCl3) δ 0.88-1.06 (m, 6H), 1.11-1.23 (m, 7H), 1.24-1.28 (m) and 1.55-1.65 (m, 1H), 1.36-1.45 (m, 2H), 1.50 (t, 3H), 1.74-1.81 (m, 1H), 2.23-2.30 (m) and 3.12-3.20 (m, 1H), 2.81 (t, 2H), 2.96 (q, 2H), 3.22-3.35 (m, 1H), 3.32 (dd) and 3.62 (dd, 1H), 4.03-4.07 (m) and 4.63-4.67 (m, 1H), 4.13 (q, 2H), 4.45 (dt, 2H), 7.32-7.46 (m, 2H), 7.84 (d, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C:19]2[CH:20]=[N:21][C:22](=[O:25])[NH:23][CH:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[BH3-]C#N.[Na+]>C(O)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([C:19]2[CH2:24][NH:23][C:22](=[O:25])[NH:21][CH:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cnc(=O)[nH]c2)cc1OC1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C2=CNC(=O)NC2)cc1OC1Cc2ccccc2C1
Yield: 86.5 %

Procedure:
5-[3-(Indan-2-yloxy)-4-methoxyphenyl]-1,2-dihydro-2-pyrimidinone (740 mg, 2.2 mmol) is dissolved in 10 ml. acetic acid cooled in an ice bath and treated with NaCNBH3 (140 mg, 2.2 mmol). The reaction is stirred for hours and is worked up by dilution with water and extraction with ethyl acetate. The collected organics are washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 640 mg (87.4%) of the title product as a white crystalline solid.
Reaction SMILES: C(CC(OC1C=[C:10]([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2S3)[CH:11]=[CH:12][CH:13]=1)=O)(O)=O.C([OH:28])C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:19]1([NH:20][C:16]([NH:15][CH:14]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:21]2)=[O:28])[CH2:18][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)CC(=O)Oc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4 g of 2-(m-carboxyacetoxyphenyl)imidazo[2,1-b]benzothiazole, 0.52 g of ethanol, and 50 ml of tetrahydrofuran was added a mixture of 2.3 g of dicyclohexylcarbodiimide and 10 ml of tetrahydrofuran at a temperature below 10° C. Thereafter, the mixture was stirred overnight at room temperature. Dicyclohexyl urea thus formed was filtered off and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography (80 ml of silica gel, eluate: a mixture of toluene and ethyl acetate (9:1)) to provide 2.0 g of oily 2-(m-ethoxycarbonylacetoxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B.C[OH:45]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=4)[C:38]([NH2:39])=[O:45])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a solution of N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.50 g, 0.87 mmol) in dichloromethane (DCM) (10 mL) at −78° C. was added a solution of borane tribromide (BBr3) (1.74 mL, 1.0 M in DCM). The mixture was stirred at −78° C. for 0.5 hour, then room temperature for one hour. The mixture was then cooled to −78° C. and methanol (1 mL) was added. The resulting mixture was stirred at room temperature overnight. Solvent was removed in vaco, the residue was treated with a 1:1 mixture of dichloromethane and water (50 mL). Organic layer was separated, dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to afford 0.019 g (4%) of the title compound as a yellow solid. M.p.=168-170° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.10 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.94-7.80 (m, 1 H), 7.77-7.65 (m, 4H), 7.53 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.25-7.13 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.34 (d, J=5.6 Hz, 1H), 3.92 (bs, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=11.2 Hz, 1H), 2.48-2.43 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H). LCMS: 595 [M+H].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][F:35]>CS(C)=O.O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][F:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nc(COCc2ccccc2)n(CF)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
In dimethylsulfoxide (20 ml) was dissolved 814 mg (2.0 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (16a), with cooling to 0 to 3° C., followed by addition of 1.44 g (10.4 mmol) of potassium carbonate with stirring, and the mixture was stirred at the same temperature for 15 minutes. Then, 270 mg (2.40 mmol) of bromofluoromethane was added, and the mixture was stirred for 30 minutes at the same temperature and then for 3 hours at room temperature, and left overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the crude product was fractionated by silica gel column chromatography (ethyl acetate:methylene chloride=1:19). From the first fraction, 137 mg (yield 16%) of positional isomer (17x') of the target compound was obtained as oil. From the subsequent fractions 700 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-fluoromethyl-4-isopropyl-1H-imidazole (17x) of the target compound was obtained as oil (yield 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1.[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:47](=[O:48])[N:25]3[C:26]([C:35]([O:37]CC4C=CC(OC)=CC=4)=[O:36])=[C:27]([C@@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+:65].[Na+].[Na+]>ClCCl>[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:47](=[O:48])[N:25]3[C:26]([C:35]([O-:37])=[O:36])=[C:27]([C@@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.[Na+:65]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Aluminium chloride (162mg, 1.21mmol) was added to anisole (7ml) and dry dichloromethane (3.5ml) at -20° C. and stirred for 15 min. The temperature of the cooling bath was then lowered to -40° C. before addition of a solution of 4-methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (235mg, 0.41mmol) in dichloromethane (5ml). After 10 min., the solution was treated with trisodium citrate (0.5M, 12ml) and then vigorously stirred for 10 min at room temperature. The aqueous phase was separated, washed with dichloromethane (x2) and concentrated in vacuo. The residue was chromatographed on HP20SS eluting with water, then 1% THF in water. Fractions containing the product, (h.p.l.c. analysis), were combined and freeze-dried to give the title compound (126mg, 65%); vmax (KBr) 3401, 1761, 1669, 1603, 1533, 1040cm-1 ; δH (d6 -DMSO, 250MHz) 1.43-1.59 (1H, m), 1.71-1.88 (2H, m), 2.0-2.12 (1H, m), 3.18 and 3.37 (2H, ABq, J 17.4Hz), 3.58 (1H, m), 3.78 (1H, m) , 3.81 (3H, s), 4.87 (1H, dd, J 8.7, 6.7Hz), 4.97 (1H, d, J 4.7Hz), 5.50 (1H, dd, J 8.1, 4.7Hz), 6.74 (1H, s), 7.21 (2H, br. s, exch.), 9.48 (1H, d, J 8.1Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (476), MNa+ (498)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[C:10](Br)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1.[CH3:14][N:15](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[OH:1][CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[C:10]([C:14]#[N:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: OCCC1COc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(CCO)CO2
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a mixture of zinc cyanide (1.97 g, 17 mmol) and (Ph3P)4Pd (498 mg, 0.4 mmol) is added 3-(2-hydroxy-ethyl)-5-bromo-2,3-dihydro-benzofuran (reference example 14, 1.1 g, 4.3 mmol) in DMF (12 mL). The resulting mixture is heated to 75° C. and stirred at this temperature for 14 hr. The reaction mixture is then allowed to cool then diluted with ethyl acetate, washed with 5% aq. ammonia solution then brine. The organic phase is dried over Mg SO4 then concentrated. The residue is purified by flash chromatography (50% ethyl acetate in hexanes) to give the product (653 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[NH:17]1>N1C=CC=CC=1>[CH3:15][CH:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]2)[N:17]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12]
Reactant: CC1CCc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC1C=Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
2-Naphthalenesulfonyl chloride (0.33 g, 1.45 mmol) was added to a solution of the tert-butyl 4-(1,2,3,4-tetrahydro-2-methylquinolin-5-yl)piperazine-1-carboxylate prepared in example 7 (0.4 g, 1.2 mmol), in pyridine (3 mL). The resulting mixture was heated under reflux for 3 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (using CH2Cl2 eluent). Yield: 0.26 g (41.2%). Rf=0.7 (CH2Cl2-acetone 98:2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][CH2:32][N:33]([CH3:35])[CH3:34].Cl>O>[Cl:22][C:3]1[C:2]([NH:1][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)CCNc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Temperature: 138 °C

Procedure:
A mixture of the amino compound from Example 54 (0.10 g), potassium carbonate (0.087 g) and N-(2-chloroethyldimethylamine hydrochloride was stirred and heated at 138° C. for 72 hr. The residue was dissolved in water and the product extracted into ethyl acetate. The organic extract was washed with brine, dried over sodium sulphate (Na2SO4) and concentrated to give an oil which was purified by Supercritical Fluid Chromatography eluting with CO2/methanol/0.1% diethylamine to give an oil. Addition of excess ethereal hydrogen chloride solution gave a solid which was triturated under an ether/ethanol/dichloromethane mixture to give a colourless powder (0.04 g).