Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:19].[CH3:20][C:21]1[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH:23][N:22]=1.CN(C=O)C.[F-].[K+]>C(OCC)(=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>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[C:3]([CH3:19])=[CH:4][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc(Cl)c(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cnc(-c2ccnc(C)c2)c(C)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction flask containing diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate 156-3 (1.00 g, 4.00 mmol), 2-methyl-4-(tributylstannyl)pyridine (1.53 g, 4.00 mmol) and Pd(PPh3)4 (440 mg, 0.4 mmol) under argon was added DMF (20 mL). The mixture was stirred at 120° C. for 10 hours. After the mixture was cooled down to room temperature, 1N KF aqueous solution was added to it and stirred for 15 minutes. The mixture was diluted with ethyl acetate and the two layers were separated. The organic layer was further washed with water and brine, dried over Na2SO4, concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give diethyl 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)malonate 156-4 as colorless oil. MS m/z 343.1 (M+1)
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18]C>CCN(CC)CC.[Cu]I>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Nc1cccc(F)c1Br
Reactant: CC#CC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et3N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)3Cl2 (500 mg) successively at room temperature under N2. The mixture was heated at 80° C. overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL×3). The organic layers were washed with sat. NaCl, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.6, 1H), 7.95 (s, 1H), 7.21 (m, 1H), 6.77 (t, J=7.6 Hz, 1H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:30][CH2:31][C:32]#[N:33])=[C:26]([N+:27]([O-])=O)[C:20]=4[S:19](=[O:35])(=[O:34])[N:18]=3)[C:7]2=[O:36])[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O1CCCC1.O.[Fe]>[NH2:27][C:26]1[C:20]2[S:19](=[O:35])(=[O:34])[N:18]=[C:17]([C:8]3[C:7](=[O:36])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[CH:23]=[CH:24][C:25]=1[O:30][CH2:31][C:32]#[N:33]
Reactant: N#CCOc1ccc2c(c1[N+](=O)[O-])S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#CCOc1ccc2c(c1N)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 60 °C
Yield: 41.6 %

Procedure:
A mixture of the product of Example 388A (13 mg, 0.025 mmol), iron powder (6.0 mg, 0.107 mmol), and ammonium chloride (1.5 mg, 0.028 mmol) in methanol:tetrahydrofuran:water (2:2:1, 2 mL) was heated at 60° C. for 1 hour. The solution filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered washed with water and dried to give title compound (5 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=1.11 Hz, 2 H) 0.41 (d, J=5.88 Hz, 2 H) 1.01 (m, 1 H) 2.85 (d, J=5.40 Hz, 2 H) 5.23 (s, 2 H) 5.80 (s, 2 H) 6.45 (s, 1 H) 6.83 (d, J=8.46 Hz, 1 H) 7.38 (d, J=8.46 Hz, 1 H) 7.44 (t, J=7.02 Hz, 1 H) 7.90 (t, J=7.02 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.16 (d, J=7.74 Hz, 1 H) 13.93 (s, 1 H) 14.94 (s, 1 H). MS (ESI−) m/z 479 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH2:11]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COC(=O)Nc1ccc(N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(N)cc1
Reaction time: 2 h

Procedure:
Intermediate 10A (2.6 g, 9.77 mmol) was deprotected with 30% TFA in DCM (40 mL). After 2 h, the reaction was concentrated and the residue was partitioned with EtOAc (75 mL) and saturated NaHCO3 (50 mL). The organic layer was washed with brine (20 mL) and dried (MgSO4). Crude Intermediate 10B was carried onto the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (1 H, s), 7.56 (2 H, d, J=8.84 Hz), 7.28 (2 H, d, J=8.84 Hz), 6.90 (2 H, s), 3.68 (3 H, s) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([N:19]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C@@H:8]([NH2:7])[CH2:9][CH3:10])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
To a solution of [(S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)propyl]carbamic acid tert-butyl ester (1.27 g, 3.60 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford the title compound as a brown oil (440 mg, 40% over 3 steps). 1H NMR (CDCl3, 400 MHz): δ 8.34 (1H, d, J=4.82 Hz), 8.08 (1H, d, J=8.00 Hz), 7.67-7.52 (3H, m), 7.45 (2H, d, J=7.60 Hz), 7.30-7.22 (1H, m), 3.99 (1H, t, J=6.70 Hz), 2.02-1.87 (1H, m), 1.83-1.69 (3H, m), 0.89 (3H, t, J=7.40 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: Clc1nccc2c(Br)cccc12
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1cccc2c(OCc3ccccc3)nccc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 198.1 %

Procedure:
A suspension of compound (1b) (0.242 g), benzyl alcohol (0.162 g), potassium hydroxide (0.224 g), potassium carbonate (0.138 g), and tris(2-(2-methoxyethoxy)ethyl)amine (0.032 ml) in toluene (6 ml) was stirred at 120° C. for 1 hour. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (1c) (0.621 g, 99%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:25])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[CH3:24])[CH:12]=[CH:13]2)=[C:8]([CH:26]2[CH2:28][CH2:27]2)[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:26]1([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:25])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:24])[CH:12]=[CH:13]3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3C)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(O)ccc1-c1ccn2c(=O)c(C(=O)O)cc(C3CC3)c2c1C
Temperature: 60 °C

Procedure:
A solution of 1-cyclopropyl-8-(4-hydroxy-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (60 mg, 0.159 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (27 mg, 0.642 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 48 as yellow solid (21 mg, 38%). ESI-MS m/z: 350 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.38 (d, J=7.2 Hz, 1H), 8.30 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.59-7.56 (m, 4H), 5.41 (t, 1H), 4.64 (d, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.81 (m, 2H).
Reaction SMILES: CN1CCOCC1.C(N=C=NCCCN(C)C)C.[CH3:19][CH:20]([CH3:43])[C@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[CH3:45][O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH2:51][S:52][CH3:53])[NH2:49].O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:45][O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH2:51][S:52][CH3:53])[NH:49][C:32](=[O:34])[C@H:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH:23][CH2:22][C@@H:21]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:20]([CH3:19])[CH3:43]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(C)[C@@H](CN[C@@H](Cc1ccccc1)C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 79.5 %

Procedure:
N-Methyl morpholine (4.0 ml) and 1-ethyl-3-(3-dimethylaminopropyl) carbodimide (EDC) hydrochloride (0.96 g, 0.005 mole) were added to a solution of the product of Step B (1.76 g, 0.005 mole), methionine methyl ester hydrochloride (1.0 g, 0.005 mole) and 1-hydroxybenzotriazole hydrate (HOBT,0.677 g, 0.005 mole) in dimethylformamide (DMF, 30 ml) the reaction mixture was stirred at room temperature over the weekend, concentrated in vacuo and taken up in ice, water, and ethyl acetate. After addition of 10% aqueous citric acid, the ethyl acetate solution was separated, washed with water (2×), aqueous NaHCO3 and brine, and dried over sodium sulfate. Filtration and evaporation of the ethyl acetate solution gave a pale yellow residue, which was purified by column chromatography (silica gel) using 35% ethyl acetate-hexane. The title compound (1.97 g) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:28].[CH3:29][N:30](C)C(=O)C.O.[OH-].[NH4+]>[Cl-].[NH4+].ClCCl.[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(N(CC)CC)C.CC(C)=O>[F:28][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH:15][N:16]=3)[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:29]#[N:30]
Reactant: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
6-((2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 200 g, 0.461 mol), zinc cyanide (ZnCN2, 32.7 g, 0.277 mol, 0.6 equiv), zinc powder (Zn, 6.0 g, 0.093 mol, 0.2 equiv) and Pd(dppf)2Cl2 (22.6 g 0.028 mol, 0.06 eqiv) were suspended in premixed solution of N,N-dimethyl acetamide (DMAC, 2000 mL) and water (H2O, 40 mL). The resulting suspension was then degassed with a stream of nitrogen for 20 min before being heated to 110° C. and stirred at 110° C. for 1-2 h (homogeneous solution was observed). When LC/MS indicated the reaction was deemed complete, the reaction mixture was cooled first to room temperature and then in an ice bath to 5° C. The cooled reaction mixture was diluted with a mixture of the saturated aqueous ammonium chloride solution (aq. NH4Cl), the concentrated ammonium hydroxide aqueous solution (aq. NH4OH), and water (4:1:4 by volume, 8.1 L) and the resulting mixture was stirred at room temperature for 30 min. The resulting solids were collected by filtration and dried in a vacuum oven overnight at 45° C. to afford the crude desired product (13). This crude material was then purified by flash chromatography (SiO2, gradient elution with 1% triethylamine in dichloromethane, 2.5% acetone and 1% triethylamine in dichloromethane, 5.0% acetone and 1% triethylamine in dichloromethane, and 10.0% acetone and 1% triethylamine in dichloromethane sequentially) to afford the pure 2-fluoro-4-(7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile (13, 127.4 g, 175.4 g theoretical, 72.6% yield) as yellow solids. For 13: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.81 (dd, 1H, J=4.15, 1.66 Hz), 8.26-8.12 (m, 4H), 8.02 (s, 1H), 7.95-7.93 (m, 2H), 7.76 (dd, 1H, J=8.71, 2.08 Hz), 7.47 (dd, 1H, J=8.70, 4.15 Hz), 4.62 (s, 2H); C22H13FN6 (MW 380.38), LCMS (EI) m/e 381.0 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)cc2[nH]ccc12
Temperature: 25 °C
Yield: 119.9 %

Procedure:
6-Bromo-4-nitro-1H-indole (1 g, 4.15 mmol) was treated with iron powder (1.16 g, 20 mmol) in acetic acid (60 ml) and stirred at room temperature. After 1 h the crude was filtered over Celite and the solvent was removed under reduced pressure. A mixture of a solution of sodium bicarbonate (4%) and ethyl acetate was added and the resulting mixture was filtered over Celite. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was removed to give 1.05 g (100% yield) of the title compound as a dark solid, that was used in the next step without further purification. Purity 83%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([CH3:15])[C:13]#[CH:14].N1CCCCC1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:14]#[C:13][C:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)([CH3:15])[CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Yield: 95.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step C of Example 3, using 1.3 grams (0.005 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 1.6 grams of (0.008 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne (prepared as in Step F of Example 17), 0.3 gram of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram of copper iodide, and 8 mL of piperidine in 20 mL of N,N-dimethylformamide, yielding 1.6 grams of 2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butynyl]pyrimidine, mp 153°-157° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].C(O[CH:26](OCC)[CH2:27][N:28]=[C:29]=[N:30][Si](C(C)(C)C)(C)C)C.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:29]3[NH:28][CH:27]=[CH:26][N:30]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: CCOC(CN=C=N[Si](C)(C)C(C)(C)C)OCC
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
To a mixture of t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate (3.3 g.) and 1-(2,2-diethoxyethyl)-3-t-butyldimethylsilylcarbodiimide (2.0 g.) in CH2Cl2 (50 ml.) at room temperature was added trifluoromethanesulphonic acid (0.89 ml.) over 2 minutes. The mixture was evaporated to dryness and the residue, t-butyl 3-acetoxymethyl-7-[2-(2,2-diethoxyethyl)-3-t-butyldimethylsilyl]guanidinoceph-3-em-4-carboxylate, was dissolved in acetonitrile (50 ml.) and the mixture treated first with 50% w/v aqueous HF (0.8 ml.) at room temperature for 15 minutes and then with 12N aqueous HCl (1.0 ml.) for 1.5 hours at room temperature. The reaction mixture was evaporated to dryness and the residue triturated with ether to give t-butyl 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate as a mixture of salts. This powder was dissolved in TFA (5 ml.) and this solution allowed to stand for 15 minutes at room temperature. The solvent was evaporated and the residue triturated with ether (yield from 7-amino derivative 41%) and then purified by chromatography on "Dowex" 1 resin (acetate form) using 0.1% v/v aqueous HOAc as eluant to give 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (yield from 7-amino derivaive 34%) having the following n.m.r. in d6DMSO: 2.1 (s, 3H); 3.45 (d, 1H); 3.7 (d, 1H); 4.8 (d, 1H); 5.15 (d, 1H); 5.3 (d, 1H); 5.7 (d, 1H); 7.1 (s, 2H); 9.4 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C)[N:20]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:14])=[O:15])=[O:29])[N:22]=1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Reactant: NS(=O)(=O)c1ccccc1-c1ccccn1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccccn2)n1
Yield: 42.3 %

Procedure:
A solution of 1.2 g of the compound from Example 2 and 1.3 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)-carbamate in 50 ml of methylene chloride was stirred under nitrogen and 3.4 ml of a 2N solution of trimethylaluminum in toluene was added. After heating at reflux for 4 days, the solution was cooled to 0°, 3 ml of 2N HCl (aq.) was added, the mixture was partitioned between methylene chloride and water. The organic layer was concentrated and the residue was chromatographed on silica gel to afford 0.9 g of the product, m.p. 175°-176°. NMR (DMSO-d6)δ: 3.8 (s, 6), 6.0 (s, 1), 7.2-8.3 (m).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].C=O.S(Cl)(Cl)=O.Cl.S(=O)=O.[CH:23](Cl)(Cl)[Cl:24]>>[CH3:1][N:2]([CH3:12])[C:3]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:23][Cl:24])=[O:4]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)CNC(=O)N(C)C
Agent: C=O
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(CCl)C(=O)N(C)C
Temperature: 25 °C

Procedure:
A reaction flask was charged with 100 cubic centimeters (cc) of chloroform, 45.4 grams (g) (0.26 mole) of N,N-dimethyl-N'-carboethoxymethylurea, and 9.0 g (0.3 mole) of paraformaldehyde. While the mixture was stirred continuously at room temperature, 35.4 g (21.4 cc, 0.3 mole) of thionyl chloride in a concentrated chloroform solution was added dropwise. A rise in temperature to 34° C. was observed. Hydrogen chloride and sulfur dioxide gases evolving from the reaction mixture were trapped in a caustic solution. The product was isolated by evaporation of the solvent, to provide 53.4 g, representing essentially full conversion. The structure as shown above was confirmed by proton resonance and mass spectrometry. The refractive index of the product was nD30 =1.4782.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)[CH2:18][CH2:17]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.C([O-])(O)=O.[Na+].O>[NH:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH:19]1[CH2:20][CH2:21][N:16]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[O:9])[CH2:17][CH2:18]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Yield: 73.2 %

Procedure:
To a stirred mixture of 4-biphenyl carboxylic acid (10.0 g, 50.5 mmol) and 2-(piperidin-4-yl)-1H-benzimidazole (10.1 g, 50.5 mmol) in DCM (400 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 g, 62.7 mmol) and 4-dimethylaminopyridine (3.08 g, 25.2 mmol). After 3 h the reaction mixture is diluted with saturated aqueous NaHCO3 (200 mL) and water (100 mL). The mixture is stirred for a few minutes. The organic layer is separated, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. Trituration with EtOAc and further washing with EtOAc gives 14.1 g of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](biphenyl-4-yl)methanone.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([NH:14]C(=O)C)=[N:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1.Cl>CO.O>[F:19][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(F)F)nc2)[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc(N)[nH]c1-c1ccc(C(F)F)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
Dissolve N-[5-[6-(difluoromethyl)-3-pyridyl]-4-methyl-1H-imidazol-2-yl]acetamide (0.172 g, 0.65 mmol) in MeOH (5 mL) and water (5 mL). Heat the mixture to 60° C. Add hydrochloric acid (12 N, 5 mL, 60 mmol). Stir mixture for 2 hours at 60° C. Concentrate the mixture to a volume of about 10 mL. Adjust the pH of the aqueous solution to 8. Extract the resulting solution with EtOAc (2×20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a yellow oil (0.153 g, 100% crude yield). LCMS (m/z) 225 (M+1).