Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1COCC1>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-t-butyldimethylsilyloxybenzene (8.3 g; 29 mmol) in THF (60 ml) at -78° C. is added a solution of butyllithium in hexane (14 ml; 35 mmol) over 10 minutes. This is allowed to stir 1 hour and 2-chlorobenzoxazole (4 ml; 35 mmol) is added dropwise over 5 minutes. After stirring 15 minutes, the reaction is allowed to warm to 0° C. and is quenched with MeOH. This is then poured into 1N HCl and after stirring 1 hour is extracted with ethyl acetate. The organic extracts are dried (MgSO4) and then concentrated to yield 4-(benzoxazol-2-yl)phenol which is used directly in Step C.
Reaction SMILES: O.NN.[Br:4][C:5]1[C:6]([CH3:29])=[C:7]([CH3:28])[C:8]2[O:12][C:11]([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)([CH3:13])[CH2:10][C:9]=2[C:26]=1[CH3:27].Cl.[OH-].[Na+]>C(O)C>[Br:4][C:5]1[C:6]([CH3:29])=[C:7]([CH3:28])[C:8]2[O:12][C:11]([CH2:14][NH2:15])([CH3:13])[CH2:10][C:9]=2[C:26]=1[CH3:27]
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN1C(=O)c3ccccc3C1=O)O2
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN)O2
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Hydrazine monohydrate (87 mg, 1.73 mmol) was added to a solution of ethanol (13 mL) containing 2-[(5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (530 mg, 1.28 mmol) synthesized in Reference Example 129, and the mixture was stirred under heated reflux for 3 hours. The reaction solution was cooled to room temperature, and 6N hydrochloric acid (10 mL) was added thereto, followed by stirring under heated reflux for 1 hour. The reaction solution was cooled to room temperature, and then 1N sodium hydroxide aqueous solution was added thereto to become weakly basic, followed by extraction using diisopropyl ether. The organic layer was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by basic silica gel chromatography (hexane-ethyl acetate 80:20-0:100) to give 250 mg of the title compound (yield: 69%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.O[C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>O1CCCC1>[CH:35]([C:34]1[C:30]([O:1][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)=[N:31][N:32]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:36]
Reactant: COC(=O)c1ccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)cc1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Reaction time: 15 h
Yield: 57.6 %

Procedure:
To a mixture of methyl 4-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.77 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.41 g), tributylphosphine (0.61 g) and tetrahydrofuran (100 mL) was added 1,1-(azodicarbonyl)dipiperidine (0.76 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (0.64 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 190-191° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[CH3:11][S:12]([C:15]1[CH:41]=[CH:40][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([F:38])[F:37])[CH:31]=3)=[C:26]([CH3:39])[NH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([C:23]2[C:28](=[O:29])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([F:37])[F:38])[CH:31]=3)=[C:26]([CH3:39])[N:25]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=3)[CH:24]=2)=[O:22])=[CH:40][CH:41]=1)(=[O:14])=[O:13]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)F)c1
Reactant: N#Cc1ccc(CBr)nc1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cn1

Procedure:
Example 40 is prepared as described for example 2.1, substituting benzyl bromide with 6-bromomethyl-nicotinonitrile and substituting preparation 5 with preparation 39a. ESI mass spectrum: [M+H]+=563; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[N:4]=1.[OH-].[Na+].[F:13][CH:14]([F:16])Cl>O1CCOCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH:14]([F:16])[F:13])[CH:6]=[C:5]([CH3:10])[N:4]=1
Reactant: CSc1nc(C)cc(O)n1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1nc(C)cc(OC(F)F)n1
Temperature: 80 °C
Yield: 27.4 %

Procedure:
218.7 g (1.4 mols) of 2-methylthio-4-hydroxy-6-methylpyrimidine are suspended in 1.12 litres of dioxane, and 1500 g (11.2 mols) of 30% aqueous sodium hydroxide solution are added. The suspension is heated to 80° C., and into this hot suspension are passed, in the course of 3 hours, 242 g (2.8 mols) of difluorochloromethane. The pale yellow suspension obtained is cooled to 20° C. and filtered. The residue is washed with dioxane and dried to thus yield 210 g of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine. The filtrate is extracted with methylene chloride, and the organic phase is washed with water and concentrated by evaporation to obtain, as crystalline residue, a further 79 g of the desired product. The overall yield obtained in this manner is 289 g of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine (100% of theory), m.p. 40-42° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:26])[CH2:9][C:10]1[C:18]2[CH:17]=[C:16]([O:19][CH:20]3[CH2:22][CH2:21]3)[CH:15]=[CH:14][C:13]=2[N:12]2[CH2:23][CH2:24][CH2:25][C:11]=12)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH:20]1([O:19][C:16]2[CH:15]=[CH:14][C:13]3[N:12]4[CH2:23][CH2:24][CH2:25][C:11]4=[C:10]([CH2:9][C@@H:8]([NH2:7])[CH3:26])[C:18]=3[CH:17]=2)[CH2:21][CH2:22]1
Reactant: C[C@@H](Cc1c2n(c3ccc(OC4CC4)cc13)CCC2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)Cc1c2n(c3ccc(OC4CC4)cc13)CCC2

Procedure:
A solution of 11.81 g (S)-[2-(6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 120 mL of a 2.26 M solution of hydrochloric acid in ethyl acetate was stirred at room temperature for 2 h. The resulting suspension was diluted with 120 mL ethyl acetate and the product collected by filtration, washed with ethyl acetate and dried to constant weight under high vacuum to yield 8.65 g (S)-2-(6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine hydrochloride as white crystals melting at 214-217° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]3[N:19]([C:33]4[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=4)[C:36]#[N:37])[C:20](=[O:32])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH:22]([CH3:23])[C:16]3=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:2].[OH-:43].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O.O>[CH2:41]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]3[N:19]([C:33]4[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=4)[C:36]([NH2:37])=[O:43])[C:20](=[O:32])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH:22]([CH3:23])[C:16]3=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:42]
Reactant: CCN(CC)CCc1cccc(Nc2ncc3c(n2)N(c2cccc(C#N)c2)C(=O)N(c2ccc(OC)cc2)C3C)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CS(C)=O
Product: CCN(CC)CCc1cccc(Nc2ncc3c(n2)N(c2cccc(C(N)=O)c2)C(=O)N(c2ccc(OC)cc2)C3C)c1
Reaction time: 3 h

Procedure:
(±)-3-[7-[3-(2-Diethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.35 g; 0.60 mmol) (from Example 5b supra) was dissolved in dimethyl sulfoxide (3.5 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 1.15 mL; 1.15 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 195 μL; 1.91 mmol) was then added. The benzonitrile slowly went back into solution. After 3 hours, water was added to the reaction mixture. The product initially separated out as a gum which then solidified. The solid was collected, washed with water and dried. Recrystallization from dichloromethane-ether gave (±)-3-[7-[3-(2-diethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide. (Yield 0.30 g; 84.8%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([N+:12]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.O.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Br)cc(N)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred suspension of 4-bromo-2,6-dinitroaniline (110 g, 420 mmol) in HCl conc (2200 mL) at −20° C. was added tin(II)chloride dihydrate (568 g, 2519 mmol, 6 eq) in one portion under cooling. After stirring overnight ar rt, water (1000 mL) was added to the suspension, and the pH was adjusted to 10 using sodium hydroxide (50% aqueous solution). After extraction with ethyl acetate (3×2000 mL), the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vaccuo to yield 81.5 g 5-bromobenzene-1,2,3-triamine (96.1%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1.[OH-].[Na+]>Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCCCBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(OCCCBr)cc1

Procedure:
A mixture of the product of part (i) above (13 g) and 5N hydrochloric acid (200 ml) was heated under reflux for 2 h. After cooling, the mixture was basified with sodium hydroxide solution and extracted with dichloromethane. The organic phase was evaporated to give the title compound (7 g) as an oil. IR includes a peak at 3360-3450 cm-1 (NH).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:14][C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[CH:11]=1>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:1][C:11]1[C:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=2[S:14][C:10]=1[CH3:9]
Reactant: Cc1cc2c(s1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 67776.3 %

Procedure:
N-bromosuccinimide (52 mg, 0.3 mmol) was added to a solution of 238 (42 mg, 0.3 mmol) in acetonitrile (1.4 mL). The resulting mixture was stirred at room temperature for 2 days. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-5% ethyl acetate in hexane) provided 239 (47 g, 73%) as a liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=O)=[CH:24][CH:23]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[OH:44][CH:45]1[CH2:48][NH:47][CH2:46]1.Cl.C(/N=N/CCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O.CO>[OH:44][CH:45]1[CH2:48][N:47]([C:29](=[O:31])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][C@@H:17]3[CH2:18][C@@H:16]3[CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][N:8]=4)[CH2:11][CH2:12]3)=[CH:27][CH:26]=2)[CH2:46]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)nc1
Reactant: OC1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CC(O)C4)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (70 mg, 0.165 mmol), 1-hydroxybenzotriazole hydrate (37.8 mg, 0.247 mmol), 3-hydroxyazetidine hydrochloride (27 mg, 0.247 mmol) and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (44.3 mg, 0.247 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min. and triethylamine (0.078 ml, 0.556 mmol) added. The mixture was stirred at RT overnight and the mixture loaded directly onto a preparative TLC plate that was developed with 10% MeOH in EtOAc. The desired product (Rf=0.35 @ 10% MeOH in EtOAc) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.20 (d, 2H), 6.85 (d, 2H), 4.70 (m, 2H), 4.55 (broad, s, 1H), 4.22 (s, 2H), 4.10 (m, 1H), 4.05 (m, 2H), 3.85 (m, 2H), 3.40 (s, 2H), 3.35 (s, 3H), 2.85 (m, 2H), 2.05 (m, 1H), 1.95 (m, 2H), 1.55 (m, 1H), 1.38 (m, 2H), 1.10 (m, 1H), 0.95 (m, 1H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 481 (M+H)+, GPR119 Human EC50: 7.7 nM.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24k (125.8 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 115.3 mg of a mixture of 24k and 25k as an off-white solid. FTIR (film) 1849.3 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([F:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a suspension of 1-bromo-2,4-difluorobenzene (53.0 mmol, 6.00 mL) in concentrated H2SO4 (38.5 mL) at 0° C. was added dropwise concentrated HNO3 (34.0 mL) maintaining internal temperature below 20° C. The resulting mixture was stirred for 10 min at 0° C., then poured into ice/water with vigorous stirring. The mixture was extracted with Et2O (3×100 mL). The combined organic extracts were washed with aqueous NaHCO3 solution (3×100 mL) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc:hexanes 1:9) to afford 5-bromo-2,4-difluoronitrobenzene as a yellow oil (12.2 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.45 (t, 1H, J=7.5 Hz), 7.16 (dd, 1H, J=11.0, 8.6 Hz); ESMS m/e: 240, 238, 223, 221, 112
Reaction SMILES: [C:1]([NH:3][C:4](=[O:7])[O:5][CH3:6])#[N:2].[C:8]1(N)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].C(O)(=O)C>O>[N:2]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:1]=1[NH:3][C:4]([O:5][CH3:6])=[O:7]
Reactant: COC(=O)NC#N
Reactant: Nc1ccccc1N
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccccc2[nH]1
Temperature: 50 °C
Yield: 72 %

Procedure:
A solution of 5.0 parts of the salt of methyl cyanocarbamate with o-phenylenediamine and 1.5 parts of acetic acid in 25 parts of water is refluxed for 30 minutes. The solution is cooled to 50° C. and filtered. The product is washed with water and dried in vacuo at 95° C. This procedure gives 3.3 parts (72% yield) of 2-benzimidazolecarbamic acid, methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2Cl2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Cl2 (40 mL) at 0° C. The resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40° C. to afford N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205° C.; 1H-NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 31H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS n/z 509 ((M+H)+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: Cc1ccc(N)nc1C
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Temperature: 140 °C
Yield: 36 %

Procedure:
A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 5,6-dimethylpyridin-2-amine (249 mg, 2.04 mmol) in acetonitrile (8 mL) and the mixture was heated in an oil bath at 140° C. for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, adsorbed on silica gel and then purified by chromatography (silica, 50 μm, 80 g column from Analogix, 0% to 10% acetone in dichloromethane, 20 min) to afford ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1H) 8.86 (s, 1H) 7.57 (d, J=8.08 Hz, 1H) 6.97 (d, J=8.08 Hz, 1H) 4.40 (q, J=7.24 Hz, 2H) 2.42 (s, 3H) 2.23 (s, 3H) 1.35 (t, J=7.20 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:17]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a solution of 1.00 g (8.05 mmol) of orcinol monohydrate and 1.63 g (7.38 mmol) of 5-fluoro-2-methylbenzenesulfonyl chloride in 20 mL of diethyl ether was added 20 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to give 2.2 g of an orange syrup. Crystallization from dichloromethane-hexane (two crops) afforded 1.24 g (54%) of the title compound as a light orange powder: 1H-NMR (300 MHz; CDCl3) δ 7.57 (dd, 1H, J=8.2, 2.8 Hz), 7.36 (dd, 1H, J=8.6, 5.2 Hz), 7.22 (td, 1H, J=8.4, 2.8 Hz), 6.52 (m, 1H), 6.39 (m, 1H), 6.30 (t, 1H, J=2.2 Hz), 2.69 (s, 3H) and 2.21 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:34]1[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Reactant: OB(O)c1cccnc1F
Product: COc1ccc(C2(c3ccc(F)c(-c4cccnc4F)c3)N=C(N)c3ccccc32)cc1C
Yield: 5 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine (Example 126) as described in Example 67 Scheme #10, D in 5% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.54-8.46 (m, 1 H), 8.22-8.15 (m, 1 H), 8.05-7.84 (m, 2 H), 7.76-7.55 (m, 5 H), 7.53-7.41 (m, 1 H), 7.32-7.23 (m, 2 H), 7.08-6.78 (m, 3 H), 3.93 (s, 3 H), 2.27 (s, 3 H); MS (ESI) m/z 442 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[C:35]([C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:46]=1[OH:47])[CH:42]=O)([CH3:38])([CH3:37])[CH3:36]>C1C=CC=CC=1.ClCCl>[C:48]([C:45]1[CH:44]=[C:41]([CH:40]=[C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:46]=1[OH:47])[CH:42]=[N:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)([CH3:50])([CH3:51])[CH3:49]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: c1ccccc1
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1

Procedure:
A solution of diphenylmethyl 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (9.89 g) and 3,5-di-t-butyl-4-hydroxybenzaldehyde (5.62 g) in a mixture of benzene (160 ml) and dichloromethane (40 ml) is refluxed for 1 hour in the presence of a molecular sieve to give a solution of diphenylmethyl 7β-(3,5-di-t-butyl-4-hydroxy-benzylidene)amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate.