Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([O:28]C)=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[C:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]=2[O:34][CH3:35])=[O:14])=[C:11]([F:38])[CH:10]=1)C1C=CC=CC=1.Br>CC(O)=O>[C:30]([C:18]1[C:17]([O:34][CH3:35])=[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][C:11]=2[F:38])[CH:21]=[C:20]([C:22]2[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc(OCc3ccccc3)cc2F)c(OC)c(C(C)(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: COc1c(NC(=O)c2ccc(O)cc2F)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
step 2—To a solution of 322 (88 mg, 0.171 mmol) and HOAc (3 mL) in a 2-5 mL microwave tube was added 48% HBr (0.037 mL, 0.684 mmol). The tube was sealed and heated to 60° for 4 h then to 40° overnight. The reaction was still incomplete so heating at was continued for 6 h at 70°. The reaction was cooled to RT, concentrated and stirred with dilute aq. K2CO3, then twice extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude product was purified on a SiO2 TLC plate developed with 75% EtOAc/hexane to afford 25 mg (965%) of I-252 as a white solid: MS (M+H)=411.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[OH-].[Na+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccn1
Reactant: N#CCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylacetonitrile 46.8 grams (0.40 mole) was added dropwise to a stirred suspension of 31.2 g. (0.80 mole) of powdered sodium amide in 200 ml. of dry toluene in an oven-dried, 2-liter, three-neck round bottom flask, equipped with dropping funnel, thermometer, stirrer and sodium hydroxide-protected condenser. During the addition, the temperature was maintained at 30°-35°C. with ice bath cooling. Afterwards, the mixture was brought slowly to reflux and maintained there for 41/2 hours with continuous stirring. Then 63.6 grams (0.40 mole) of 2-bromopyridine in 100 ml. of toluene was added dropwise at a rate which maintained refluxing of the solution. After complete addition, stirring and refluxing was continued for 3 hours. The mixture was then cooled at 25°C. and ca. 300 ml. of water was added, at first very cautiously and then in a steady stream. The phases were separated and the toluene layer extracted with ca. 150 ml. of water, and then with several portions of cold 6 N hydrochloric acid. The acid extracts were basified with 50% sodium hydroxide with cooling and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and concentrated, and the residue was distilled. Yield, 41.7 g. (54 %); b.p. 134°-136°C./0.07 mm. The distillate crystallized and after recrystallization from isopropyl ether melted at 87°-88.5°C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.B.[OH:18]O>>[OH:18][CH2:1][CH:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:3]1
Reactant: C=C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: OO
Agent: B
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC2C1

Procedure:
Methods for the synthesis of suitable 3-azabicyclo[3.3.0]octane intermediates vary. For instance, Flynn et al., Tetrahedron 53(1): 1-20 (1996), provides two approaches to suitably functionalized 3-azabicyclo[3.3.0]octanes. Such reference is herein incorporated by reference with regard to such synthetic teaching. The first approach involves the palladium-catalyzed [3+2] cycloaddition reaction of 2-trimethylsilylmethyl-2-propen-1-yl acetate with dimethyl maleate. The resulting diester is saponified, treated with acetic anhydride, and pyrolyzed to give the fused cyclic anhydride, tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione. Treatment with ammonia followed by cyclization with acetyl chloride gives the imide, tetrahydro-5-methylene-1H-cyclopenta[c]pyrrole-1,3(2H,2aH)-dione. Reduction with lithium aluminum hydride and protection of the free amine with di-tert-butyl dicarbonate gives 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Subsequent transformations, using this methylene compound, are possible. For instance, ozonolysis of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane will give 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one. Alternately, treatment of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane with borane, followed by aqueous basic hydrogen peroxide, will produce 7-(hydroxymethyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Oxidation of this alcohol by any number of methods, known to those of skill in the art of organic synthesis, will generate 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, a key intermediate for the synthesis of compounds of the present invention.
Reaction SMILES: [N:1]1([C@@H:7]([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[OH-].[Pd+2].[OH-].[C]>[N:1]1([C@@H:7]([CH3:18])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@@H](C(=O)OCc1ccccc1)N1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](C(=O)O)N1CCOCC1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
Under an argon atmosphere, to a solution of benzyl (S)-2-(morpholin-4-yl)propionate (43 g, 172 mmol) in methanol (430 ml) was added 20% palladium hydroxide-carbon (4.3 g) at room temperature, and the mixture was stirred for 3 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (25.4 g, 93%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1B(O)O.C[N+]1([O-])CC[O:29]CC1.CCCCCC>C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[OH:29]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(F)c(B(O)O)cc1SCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(O)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To 300 ml of toluene were added 32.0 g (119 mmol) of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl boronic acid produced by the method described in PCT International Publication No. WO 2007/034755 and 15.4 g (131 mmol) of N-methylmorpholine-N-oxide, followed by refluxing for 1 hour under heating. The reaction mixture was allowed to cool to room temperature. The solvent was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic phase obtained was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=4:1), to obtain 25.5 g (yield: 89%) of an intended product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A sealed 8 mL vial is charged with a solution of 4-[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-pyridin-2-ylamine (11 mg, 0.041 mmol) in methylene chloride (2 mL). Then benzoyl isocynate (9.0 mg, 0.06 mmol) is added. The resulting mixture is allowed to stir at 50° C. for 1 hour. The solvent is then carefully removed before potassium carbonate (6.8 mg, 0.049 mmol) and ethanol (1 mL) are added. The resulting reaction is allowed to stir at 85° C. for 30 min. Solvent is removed and the crude is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 5%) to give 11 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>CC(C)=O>[CH3:13][O:14][C:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])=[O:16]
Reactant: COC(=O)N=C=S
Reactant: CSc1ccc([N+](=O)[O-])c(N)c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(SC)ccc1[N+](=O)[O-]
Reaction time: 120 h

Procedure:
1.5 G. 2-amino-4-methylthio-1-nitrobenzene in 30 ml. acetone is treated with 2.5 g. methoxy carbonyl isothiocyanate. After five days the mixture is stripped under vacuum and the residue triturated with methanol yielding 1-(3-methoxycarbonyl-2-thioureido)-5-methylthio-2-nitrobenzene.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=[CH:12][C:3]1=2.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:14][CH2:15][N:16]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:17][CH2:18]3)=[CH:10][CH:11]=[CH:12][C:3]1=2
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCCO2
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4OCCCO5)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride (J. Med. Chem. 1988, 31, 1934–1940) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 451.2 (Exact Mass: 450.23).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Li+].CC([N-]C(C)C)C.CN([CH:34]=[O:35])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:34]=[O:35])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCn1cc(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Yield: 29.9 %

Procedure:
Reaction of 4-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (170 mg, 0.53 mmol), 0.53 M LDA (1 mL, 0.53 mmol), and DMF (232 uL, 1.60 mmol) for 4 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (55 mg, 30%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.63 (t, 2H, J=9.0 Hz), 5.82 (s, 2H), 7.79 (s, 1H), 7.98 (d, 2H, J=9.0 Hz), 8.27 (d, 2H, J=9 Hz), 9.89 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:37])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].[Li+].[OH-].Cl>CO.O>[C:33]([O:32][C:30]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21](/[CH:20]=[CH:19]/[C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH2:5][CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])[C:3]([OH:38])=[O:2])=[CH:18][CH:17]=1)=[O:37])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(CCC1CCCN1C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCCC1CCC(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(1-methyl-pyrrolidin-2-yl)-butyric acid methyl ester (52.1 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol.) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid product without further purification. MS: calc'd 508 (MH+), exp 508 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>C(Cl)Cl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Product: Clc1ncc2ccccc2n1

Procedure:
A solution of 2,4-dichloroquinazoline (5 g) in methylene chloride (100 mL) is combined with 100 mL of saturated brine containing 9% NH4OH and powdered zinc (5 g). The resultant mixture is refluxed for 4 hours, cooled and filtered through celite. The organic layer is removed, diluted with ethyl acetate (100 ml), washed with 1 N HCl solution, dried and concentrated to yield 2-chloro-quinazoline.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([N:8]([CH2:16][C:17]2[CH:37]=[CH:36][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C@H:27]3[NH:31][C:30](=[O:32])[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:9]([N:8]([CH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:35]=[CH:34][CH:33]=[C:24]([O:25][CH2:26][C@@H:27]3[CH2:28][CH2:29][C:30](=[O:32])[NH:31]3)[CH:23]=2)=[CH:19][CH:18]=1)[C:4]1[C:3]([CH3:38])=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OC[C@@H]3CCC(=O)N3)c2)cc1
Reaction time: 3 h

Procedure:
The dried product from example 278B was dissolved in anhydrous pyridine (3 mL) at 0° C. for 30 minutes. Then methanesulfonyl chloride (50 μL, 6 mmoles) was injected. The reaction mixture was let to stand at room temperature for 3 hours. Then the reaction mixture was dried in vaccuo, dissolved in CH2Cl2 (4 mL), filtered and dried in vaccuo. The final residue was purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 7.76 (s, 1 H), 7.27 (m, 7 H), 7.20 (m, 1 H), 7.04 (m, 1 H), 6.95 (m, 4 H), 6.71 (m, 1 H), 6.53 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.92 (m, 1 H), 3.82 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.04-2.29 (m, 3 H), 1.80 (m, 1 H); MS (APCI+) m/z 586 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>ClCCl>[Br:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1cccnc1N
Reactant: O=S(=O)(Cl)c1ccc(CCBr)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
3-Methyl-2-pyridinamine (431 g, 4.0 mol) was dissolved in dichloromethane (700 ml) and 4-(2-bromoethyl)benzenesulfonyl chloride (340 g, 1.33 mol) was added at room temperature. After 1 h at 20° C., the solution was heated to 35° C. for 2 h. Excess dilute hydrochloric acid was added and the phases separated. After washing once with water, the organic phase was dried with MgSO4 and treated with decolorizing carbon. The solvent was evaporated and warm methanol added to the residue, which crystallized. The material was collected and recrystallized from toluene. Yield 178 g. A further crop of 36 g was obtained by workup of the mother liquor. Total yield 45%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc(Cl)c2cccnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ccccc3o2)c2cccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a stirred solution of 5-chloro-8-methoxy-quinoline (0.330 g, 1.70 mmol) in THF (2 mL) at room temperature was added benzofuran-2-boronic acid (0.413 g, 2.55 mmol) followed by KF (0.296 mL, 5.10 mmol), Pd(OAc)2 (0.0382 g, 0.170 mmol), and 2-(di-tert-butyl phosphino)biphenyl (0.101 g, 0.340 mmol). The reaction mixture was stirred at room temperature for 18 hours and then diluted with EtOAc (200 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) then dried (Na2SO4). After concentration, the residue was purified on a Biotage Flash 40 apparatus (30-70% EtOAc:petroleum ether) to afford the product (0.291 g, 62%) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 276. 1H NMR (500 MHz, DMSO-d6): δ 8.94 (d, 1H, J=2.2 Hz), 8.83 (d, 1H, J=9.4 Hz), 7.99 (d, 1H, J=8.6 Hz), 7.66-7.77 (m, 3H), 7.27-7.41 (m, 4H), and 4.6 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[BH4-].[Na+]>C1COCC1.C(O)(C)C>[F:1][C:2]1[N:3]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was dissolved in a 2:1 (v/v) mixture of THF and isopropanol and treated with sodium borohydride at 20°. After 5 minutes the reaction was quenched with water. Extractive work-up and final trituration with MeOH gave 2-fluoro-4-hydroxymethyl-1-triphenylmethylimidazole. This was reacted with methanesulphonyl chloride and triethylamine in CH2Cl2 at ambient temperature to give 4-chloromethyl-2-fluoro-1-triphenylmethylimidazole. This was treated at ambient temperature in a water/THF solution with sodium azide, and crude product deprotected with toluene-p-sulphonic acid in CH2Cl2, to give 4-azidomethyl-2-fluoroimidazole as its toluene-p-sulphonate salt. This was reacted at 60° for 4 hours in DMF with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate. The product was purified by silica gel chromatography at -20°, using as eluant CH2Cl2 /MeOH/HOAc 96:2:2 v/v/v, to give t-butyl 3-acetoxymethyl-7-(4-azidomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following i.r. spectrum: νmax (film) 1680; 1725; 1745; 1790; 2110 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:23](B(O)O)=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[CH:25]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([C:23]3[C:22]([CH3:21])=[CH:30][CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][NH:27]4)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reactant: Cc1ccc2[nH]ncc2c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(-c2c(C)ccc3[nH]ncc23)nc2c1CN(Cc1ccccc1)CC2
Temperature: 140 °C

Procedure:
A mixture of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.09 g, 3.75 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (600 mg, 3.41 mmol), Pd(PPh3)4 (197 mg, 0.170 mmol), and Na2CO3 (2 M, 5.97 mL, 11.9 mmol) in DME (11 mL) was heated in a microwave reactor at 140° C. for 1.5 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (20-100% EtOAc/heptane) to provide 6-benzyl-4-methoxy-2-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 386.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH:19]=[CH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1)[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of N-tertiary-butyloxycarbonyl-N-methyl4-iodoaniline (11 g, Reference Example 9), tert-butyl acrylate (8.4 g), tris-(o-tolyl)phosphine (500 mg), palladium (II) acetate (150 mg), and triethylamine (7 g) in DMF (20 mL) was stirred at 90° C. under nitrogen overnight. The reaction mixture was cooled to room temperature then partitioned between ethyl acetate (500 mL) and hydrochloric acid solution (500 mL, 1M). The organic phase was dried and then evaporated. The residue was crystallised from cyclohexane to give the title compound (7.4 g) as a white solid.