Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7](Cl)=[N:8][CH:9]=1.[C:14](OCC)(=O)CC(OCC)=O>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([CH3:14])=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
Sodium hydride (1.31 g, 54.8 mmol, 2.19 g of 60% in mineral oil) was suspended in dry THF (70 mL) and to this suspension was added 5-bromo-2-chloro-3-nitropyridine as a solid. An ambient water bath was placed under the reaction and a solution of diethyl malonate in dry THF (15 mL) was added carefully via addition funnel. Observed a vigorous evolution of gas. After 2 hours additional sodium hydride (0.202 g, 8.42 mmol, 0.337 g of 60% in mineral oil) was added and the reaction was stirred for 1.5 hours. The reaction was concentrated in vacuo, diluted with 6N HCl (100 ml), and refluxed overnight. The reaction was concentrated in vacuo and diluted with saturated sodium carbonate to pH 9. The basic aqueous mixture was diluted with dichloromethane and filtered through filter paper to remove an insoluble green solid. The filtrate was transferred to a separatory funnel and the layers were separated. The dichloromethane was washed with saturated sodium chloride (aq), dried over sodium sulfate, filtered and concentrated to give the title compound (5.79 g, 63.3%) as an orange oil. MS(ES)+ m/e 217 [M+H].
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:43]=[CH:42][C:29]([CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Cl-].[Na+].O.O>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:26]3[CH:43]=[CH:42][C:29]([CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:28][CH:27]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc(CNC(=O)OCc3ccccc3)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)OCc1ccccc1
Temperature: 65 °C
Yield: 55 %

Procedure:
In a 50 mL round bottomed flask, equipped with a magnetic stir bar, 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (1.0 g, 3.3 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C13) (1.3 g, 3.6 mmol), bistriphenylphosphine dichloropalladium(II) (0.120 g, 0.171 mmol), and potassium phosphate (1.38 g, 6.49 mmol) were charged as solids. The flask was sealed and placed under nitrogen atmosphere. Dioxane (17.3 mL) and water (4.3 mL) were added. The reaction was warmed to an internal temperature of 65° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into a brine solution and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash column chromatography using 0-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (0.850 g, 56%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.17-8.00 (m, 4H), 7.91 (t, J=6.2 Hz, 1H), 7.72-7.59 (m, 2H), 7.46-7.12 (m, 7H), 5.07 (s, 2H), 4.29 (d, J=6.1 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 469 ([M+H]+).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C:57]([C@H:60]2[CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61]2)([CH3:59])[CH3:58])[N:53]=[C:52]([S:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:76][C:70]1[C:71]([F:75])=[CH:72][CH:73]=[CH:74][C:69]=1[CH2:68][S:67][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C:57]([C@H:60]2[CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61]2)([CH3:59])[CH3:58])[N:53]=1
Reactant: CC1(C)OC[C@H](C(C)(C)Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)O1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)OC[C@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.20 g), tris(dibenzylideneacetone)dipalladium (0) (91 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (42 mg), cesium carbonate (0.49 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-pyrimidine (0.43 g) in dioxane (8 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a pale yellow foam. Yield: 0.43 g
Reaction SMILES: Br.CS(O)(=O)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:32])[C:13]3[C:21](=[O:22])[N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[N:19]=[C:18]([OH:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:32])[C:13]3[C:21](=[O:22])[N:20]([C:23]4[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=4)[N:19]=[C:18]([OH:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Agent: Br
Agent: CS(=O)(=O)O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)cc3)c(=O)c12
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a 50 mL solution of 5: 1 48% HBr: methanesulfonic acid was added 7-chloro-4-hydroxy-2-(4-methoxyphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.0328 g, 27.9 mM). The resulting suspension was heated to 110° C. over 3.5 hours. HPLC analysis afforded a total conversion to a new material. The suspension was cooled to room temperature and filtered through a buchner funnel. The yellow solid was washed 2x with 100 mL portions of distilled water followed by 200 mL of a 1: 1 solution of THF: ether. The material was then washed with hexanes until the yellow solid was free flowing. This solid was allowed to air dryfor 72 hours prior to submission for analysis. No percent yield was recorded for this reaction.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>[Pt].C.O1CCOCC1.C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)c1ccc([C@H]2CC[C@H](CCC3OCCO3)CC2)cc1

Procedure:
A mixture of 500 mg of 4-[4-[2-(1,3-dioxolan-2-yl)ethylidene]cyclohexyl]benzamide and 20 ml of dioxan/triethylamine (vol. 9:1) was hydrogenated in the presence of 500 mg of 10 percent platinum-charcoal for 2 hours. The reaction mixture was then filtered and the filtrate was evaporated. Recrystallization of the evaporation residue from 40 ml of dioxan gave 230 mg of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]benzamide as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[Na]>C(Cl)Cl.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C#N)c(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
2-nitro-4-benzyloxy-5-methoxybenzonitrile (40 g, 125 mmol) tetrabutylammonium chloride (21 g, 75 mmol) in methylenechloride (500 ml) was treated with Na2S2O4 (180 g, 87.9 mmol) in H2O (700 ml), sodium hydrosulfite was added over 45 minutes, and the mixture was stirred for 2 hours at room temperature. Sodium hydroxyde was added (pH 8.2) the mixture was extracted with methylene chloride. The organic phase was made acidic with HCl-ether (2.3N, 250 ml), the solid was recovered, suspended in methanol (250 ml) and treated with a saturated solution of sodium bicarbonate (pH 8.1). The solid was recovered, washed with water, ether to give title compound (30.7 g, 97%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)CCC.N[C:33]1[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][C:34]=1[C:41]#[N:42].C1(C)C=CC=CC=1>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>[C:41]([C:34]1[CH:35]=[N:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:33]=1[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)#[N:42]
Reactant: CC(C)n1ncc(C#N)c1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3c(C#N)cnn3C(C)C)nc1-2

Procedure:
A mixture of methyl 2-(tributylstannyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (155 mg, 0.291 mmol), 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (133 mg, 0.509 mmol) and Tetrakis(triphenylphosphine)palladium(0) (16.8 mg, 0.0145 mmol) in Toluene (6.0 mL, 56 mmol) was heated for 18 hours. The mixture was concentrated in vacuum, the residue purified on 4 g silica column eluting with 30% ethyl acetate in heptane. Yield 65 mg (59%). MS (ESI+): 378.2
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:43]=[CH:42][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:25][C:24]=3[O:40][CH3:41])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH2:69][CH:70]2[CH2:72][O:71]2)=[CH:64][CH:63]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:41][O:40][C:24]1[CH:25]=[C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:72][C@H:70]([OH:71])[CH2:69][O:68][C:65]3[CH:66]=[CH:67][C:62]([OH:61])=[CH:63][CH:64]=3)=[CH:43][CH:42]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 39.6 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[2-methoxy-4-(3-phenoxypropoxy)phenethyl]-1-piperidinecarboxamide formate (0.426 g, 0.718 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.29 g, 0.718 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.27 g, 0.284 mmol).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[N+:19]([O-])=O)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[H][H]>CO.C1COCC1.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Yield: 97.8 %

Procedure:
A solution of 3.0 g (9.7 mmol) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 50 mL of methanol and 50 mL of THF was treated with 0.30 g of 10% Pd/C and treated with 30 psi of hydrogen in a Parr apparatus for 1.5 h. The catalyst was removed by filtration and the red solution concentrated to give 2.65 g (98%) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.2 g, 40.3 mmol) in dry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at −78° C. for 15 min, (4-fluorophenyl)acetyl chloride (6.34 mL, 46.4 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 8.35 g (31.5 mmol, 78%) of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.25 (m, 2H), 7.10 (t, 2H, J=8.5 Hz), 4.46–4.41 (m, 1H), 4.36–4.15 (m, 4H), 2.40–2.28 (m, 1H), 0.88 (d, 3H, J=7.6 Hz), 0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.1 (M+H)+.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]([C:20]([O:22]C)=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:20]([OH:22])=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
LiOH H2O (0.2 M, 6.8 mL, 1.36 mmol) was added portionwise to a solution of crude methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (210 mg, 0.39 mmol) in THF (0.5 mL), and the mixture stirred at 40° C. for 3 h, after which time the TLC analysis showed consumption of starting material ester. The reaction mixture was diluted with aqueous NaOH solution (1 M) (50 mL) and the mixture washed with CH2Cl2 (100 mL). The aqueous layer was acidified to pH 2 with aqueous HCl solution (1 M) and was extracted with CH2Cl2 containing 30% of propan-2-ol (2×150 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, yield 75%). This crude material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2F)nc1-c1ccc(C)cc1
Yield: 58.6 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-fluorophenylboronic acid (126 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 69 mg (41%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])/[C:19](=[N:24]\[O:25][CH3:26])/[C:20](=[O:23])[CH2:21][Cl:22])[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])O.[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO.C(OCC)(=O)C>[Cl:22][CH2:21][C:20](=[O:23])/[C:19](=[N:24]/[O:25][CH3:26])/[C:18]([NH:17][CH:16]1[C:15](=[O:28])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]12)=[O:27]
Reactant: CO/N=C(/C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)C(=O)CCl)[C@H]2SC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
500 mg of 3-acetoxymethyl-7-[4-chloro-3-oxo-(Z)-2-methoxyiminobutyrylamino]-3-cephem-4-carboxylic acid and 150 mg of sodium hydrogen carbonate were dissolved in 5 ml of 67% v/v aqueous methanol, and 5 g of anhydrous calcium chloride were added thereto. The resulting mixture was stirred at 65° C. for 1 hour, after which 30 ml of ice-water and 50 ml of ethyl acetate were added to the reaction mixture. The mixture was then acidified with hydrochloric acid and the aqueous phase was separated. The aqueous phase was then extracted twice, each time with 30 ml of ethyl acetate. The extracts were combined, and the combined extracts were washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate, and then concentrated by evaporation under reduced pressure, to give 320 mg of the title compound, in the form of a pale solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])[C:5]([C:20](=[O:23])[NH:21][CH3:22])=[CH:4][N:3]=1.[F:24][C:25]1[C:26]([CH3:32])=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O>[F:24][C:25]1[C:26]([CH3:32])=[CH:27][C:28]([NH:31][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([OH:14])=[O:13])[C:5]([C:20](=[O:23])[NH:21][CH3:22])=[CH:4][N:3]=2)=[N:29][CH:30]=1
Reactant: Cc1cc(N)ncc1F
Reactant: CNC(=O)c1cnc(Cl)cc1Nc1cccc(C(=O)O)c1OC
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: CNC(=O)c1cnc(Nc2cc(C)c(F)cn2)cc1Nc1cccc(C(=O)O)c1OC
Temperature: 110 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A reaction vial was charged with 3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (600 mg, 1.787 mmol), 5-fluoro-4-methylpyridin-2-amine (316 mg, 2.502 mmol), BrettPhos (38.4 mg, 0.071 mmol) and Pd2(dba)3 (32.7 mg, 0.036 mmol) and the contents were flushed with nitrogen before adding dioxane (2 mL) and DMA (1 mL). The resulting slurry was sparged with additional nitrogen for ˜1 minutes, then LiHMDS (1 M in THF) (3.93 mL, 3.93 mmol) was added and the resulting dark amber colored solution was heated in a preheated heating block at 110° C. for 2 h, then cooled to room temperature. The reaction mixture was added to water (80 mL) and the pH was adjusted with aq. 1N HCl to ˜3 causing a solid to precipitate from solution. After stirring the slurry at room temperature for ˜4 h, the solid was collected by vacuum filtration, rinsed with water, and dried on the filter to afford 3-((2-((5-fluoro-4-methylpyridin-2-yl)amino)-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (736 mg, 1.730 mmol, 97% yield) as a beige solid. HPLC (Method N) RT=2.45 minutes. LCMS (m+1)=426.
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[CH2:11][CH2:10][C:9]2([CH:16]=[C:15]([C:17]3[CH:22]=[C:21](F)[C:20]([O:24]CC)=[C:19](F)[CH:18]=3)[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12]2)[CH2:8][CH2:7]1)([OH:4])=[O:3].C(=O)([O-])O.[Na+].[CH2:37](I)[CH3:38]>CN(C)C=O.C(OCC)(=O)C>[OH:24][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12][C:9]3([CH2:8][CH2:7][N:6]([CH2:5][C:2]([O:4][CH2:37][CH3:38])=[O:3])[CH2:11][CH2:10]3)[CH:16]=2)=[CH:18][CH:19]=1
Reactant: CCOc1c(F)cc(C2=CC3(CCN(CC(=O)O)CC3)Oc3ccccc32)cc1F
Reactant: CCI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC2(C=C(c3ccc(O)cc3)c3ccccc3O2)CC1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a mixture of 1′-Carboxymethyl-4-(4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4′-piperidine]-1′-acetate (432 mg, 1 mmol., prepared according to Example 42), sodium hydrogen carbonate (176 mg, 2.1 mmol) in dry N,N-dimethylformamide (25 cm3) was added ethyl iodide (0.088 cm3, 1.1 mmol) and the mixture was heated to 80° C. for 2 h. Upon cooling, it was diluted with ethyl acetate (100 cm3) and washed with water (5×100 cm3). The organic solution was then dried over sodium sulfate before the solvent was removed in vacuo. The crude material was then passed through a short pad of silica first with dichloromethane (which was discarded) and then with ethyl acetate. The solvent was removed to afford the desired product (194 mg, 51%).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCCN1CCC[C@@H](O)C1
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H](O)C3)cc12
Yield: 6.5 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (1.41 g) and (R)-3-(3-hydroxypiperidin-1-yl)propionitrile (1.44 g), (R)-3-[2-(3-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (147 mg) was obtained.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:27][CH2:28][O:29][CH3:30])[CH:4]=[CH:5]2>CO.[Pd]>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:27][CH2:28][O:29][CH3:30])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene (1.0 g. 2.46 mmol) is dissolved in MeOH (40 ml), mixed with 10% Pd unactivated charcoal 800 mg and then agitated at RT under H2 (1 bar over pressure) for 2 hours. The catalyst is eliminated by filtering over a filter compound and a filtrate is concentrated by rotary evaporation.