Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:14])[CH:7]=[CH:6]2)[CH3:2].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:21]1[CH2:22][O:23][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH:9]=2)([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[O:14]1
Reactant: CCc1ccc2cc(C(=O)Cn3ccnc3)ccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccc2cc(C3(Cn4ccnc4)OCCO3)ccc2c1

Procedure:
A mixture of 0.7 g. of 1-[(6-ethyl-2-naphthoyl)methyl]imidazole, 4 ml of ethylene glycol and 1.3 g. of anhydrous p-toluenesulfonic acid in 50 ml. of toluene is heated overnight under reflux through a Dean-Stark trap. Thetrap is the replaced by a separatory funnel containing 4 A molecular sievesand heating is continued for a further day. After cooling, the mixture is treated with 100 ml. of ethyl acetate, neutralized by pouring into excess aqueous potassium carbonate and the organic phase separated, washed with water, dried (MgSO4) and evaporated to afford 1-[2,2-ethylenedioxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole. This is purified by chromatography on silica gel eluting with 10% methanol/dichloromethane and the hydrochloride salt prepared by dropwise addition of ethereal hydrogen chloride until precipitation is complete. Filtration and recrystallization from acetone/methanol gives 0.38 g. pure hydrochloride, m.p. 251° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[S:11][C:12]=1[Br:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(Cc2csc(-c3ccc4c(c3)OCO4)n2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1sc(-c2ccc3c(c2)OCO3)nc1Cc1ccccc1
Reaction time: 8 h

Procedure:
367 mg of 4-benzyl-2-(3,4-methylenedioxyphenyl)thiazole was dissolved in 2 ml of N,N-dimethylformamide 244 mg of N-bromosuccinimide was added thereto under ice-cooling, followed by stirring overnight. Then, ethyl acetate was added to the reaction solution, followed by washing with water. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 3% ethyl acetate/hexane as an eluent for separation and purification, to give 377 mg of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([OH:25])=[O:24]>[Cu].C1(C)C(C)=CC=CC=1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([OH:25])=[O:24])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
xylene (600 mL), potassium carbonate (53.75 g), 4-chlorophenol (46.25 g), and copper powder (2.7 g) are charged in to a round bottom flask at 25-35° C. The reaction mixture heated to 60-70° C., o-chlorophenyl acetic acid (50 g) is added in portions. The reaction mixture is heated to reflux, maintained for 2-3 hours and simultaneously water is removed by azeotropic distillation. The reaction mixture is cooled to below 90° C. Water (600 mL) is added, both layers are separated. The organic layer is washed with water (600 mL). The combined organic layer is cooled to 0-10° C. and conc. HCl (26 mL) is added until the pH reaches to 2.0. The reaction mass is maintained at 0-10° C. for 1 hour, the obtained solid is collected by filtration, washed with water (450 mL), and dried at 60° C. to afford 33.8 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:15])=[CH:11][C:10]=1[C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102 %

Procedure:
To a solution of 4-(benzyloxy)-3-tert-butylbenzoic acid (2.36 g, 8.31 mmol) in anhyd DMF (56 mL) was added glycine t-butyl ester (1.63 g, 12.5 mmol), BOP reagent (5.51 g, 12.5 mmol), and N-methylmorpholine (2.74 mL, 24.9 mmol). The mixture was stirred at room temperature for 12 h under nitrogen atmosphere and then diluted with EtOAc (200 mL). The organic layer was washed consecutively with 1 N HCl (250 mL), satd NaHCO3 (100 mL), 5% LiCl (2×100 mL), and brine (50 mL), dried (Na2SO4), and concentrated in vacuo. tert-butyl 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetate (3.37 g, quant.) was isolated as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.63-7.60 (m, 1H), 7.46-7.34 (m, 5H), 6.95-6.93 (m, 1H), 6.52 (s, 1H), 5.16 (s, 2H), 4.14-4.11 (m, 2H), 1.51 (s, 9H), 1.41 (s, 9H); MS found: (M+H)+=398.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8]O.P(Br)(Br)[Br:16].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:16]
Reactant: OCCCCOc1cc(Br)ccc1Br
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: BrCCCCOc1cc(Br)ccc1Br
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a solution of 12.63 g (39 mmol) of 4-(2,5-dibromophenoxy)butan-1-ol in 83 mL of toluene was added 1.65 mL (17.6 mmol, 0.45 equiv) of phosphorous tribromide. The solution was stirred under nitrogen at 90° C. for 2.5 hours. Additional phosphorous tribromide (0.37 mL, 3.9 mmol, 0.10 equiv) and 0.21 ml (11.5 mmol, 0.3 equiv) of water were added, and the mixture was stirred under nitrogen at 90° C. for 8 hours. The mixture was allowed to cool to ambient temperature, 69 mL of 1N NaOH was added dropwise over 30 minutes, and the layers were separated. The aqueous layer was extracted with 25 mL of toluene. The combined organic layer was washed with 25 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a cloudy yellow oil suitable for the next step. MS (m+1)=386.1, 385.1, 381.0; 1H NMR (400 MHz, CDCl3) 7.38 (d, 1H, J 8 Hz), 6.98 (m, 2H), 4.05 (t, 2H, J 6 Hz), 3.53 (t, 2H, J 6 Hz), 2.12 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: [Na].[C:2](#[N:4])[CH3:3].[C:5](OC)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C.N>[CH3:7][C:6]([CH3:9])([CH3:8])[C:5](=[O:10])[CH2:3][C:2]#[N:4]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C)(C)C(=O)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To 2.5 l of liquid ammonia containing 2.5 g of anhydrous ferric chloride was cautiously added 132 g of sodium metal portionwise while keeping the temperature of the reaction mixture at -50° C. To this portion was added rapidly a solution of 234 g of acetonitrile diluted with 300 ml of anhydrous diethyl ether followed by the controlled addition of a solution of 332 g methyl pivaloate diluted with 300 ml anhydrous ether at such a rate that the reaction temperature did not exceed -30° C. Allowed reaction to warm up to room temperature overnight. After all of the ammonia has evaporated off, 1 kg of crushed ice is added followed by enough cold water to make the final volume 4.5 l. The mixture is stirred for 30 min., then filtered through a celite bed. The celite was washed well with cold water and 1 l of 1:1 ether/hexane. The phases were separated, discarding the organic layer. The aqueous layer was cautiously acidified with conc. HCl, cooling as necessary to keep the temperature below 35° C. The acidified aqueous phase was extracted with dichloromethane (3×500 ml). The combined organic phases were dried over MgSO4, filtered, and the solvent removed to yield 316 g of the desired product, M.P. 68° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([Si](C)(C)C)=[N+:10]=[N-:11]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:9]=[N:10][NH:11][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of phenylacetylene (1.098 ml, 10 mmol) in abs. toluene (10 ml) was added azidotrimethylsilane (2.65 ml, 20.00 mmol) in one portion. The reaction was heated at 100° C. for 3 days, whereupon was cooled to room temperature and toluene was removed by vacuum. The residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was chromatographed in petroleumether:EtOAc=2:1. (Yield: 355 mg, 24%).
Reaction SMILES: O=C1N2CCCCC2=NC=C1C([O-])=O.[Na+].CC(C)=O.ClC(OCC)=O.[CH3:26][C:27]1([CH3:49])[S:31][C@@H:30]2[C@H:32](NC([C@H](N)C3C=CC=CC=3)=O)[C:33](=[O:34])[N:29]2[C@H:28]1[C:46]([OH:48])=[O:47].O.O.O>CN1CCOCC1.[OH-].[Na+].CC(N(C)C)=O>[CH3:26][C:27]1([CH3:49])[S:31][C@@H:30]2[CH2:32][C:33](=[O:34])[N:29]2[C@H:28]1[C:46]([OH:48])=[O:47]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])c1cnc2n(c1=O)CCCC2
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: -10 °C
Yield: 234.7 %

Procedure:
Sodium 6,7,8,9-tetrahydro-4-oxo-4H-pyrido-[1,2-a]pyrimidine-3-carboxylate (2mM, 0.432g.) was suspended in a mixture of dry acetone (25ml) and dry dimethylacetamide (2ml) and chilled to -10° C with stirring. Ethyl chloroformate (2mM, 0.2ml) and one drop of N-methyl morpholine were added and the reaction mixture stirred 20 minutes at -10° C. A solution of ampicillin trihydrate (2mM, 0.726g) in aqueous sodium hydroxide (0.489N, 3.64ml) was chilled and added to the mixed anhydride at -10° C. The reaction was stirred 1.75 hours to ambient temperature, the acetone evaporated, and the resulting solution diluted to 100ml with water, covered with ethyl acetate (50ml) and adjusted to pH 2.0 with 5N HCl. The organic layer was separated, the aqueous phase extracted with ethyl acetate (1 × 50ml), the organic extracts combined, washed with water (3 × 30ml), dried over magnesium sulphate to give the penicillanic acid as a white solid 0.85g. (85%), showing a single component on t.l.c., Rf 0.51 (chloroform/acetone/acetic acid; 7:7:1) δ [(CD3)2SO] 1.4, 1.55 (6H, 2 × s, gem dimethyls), 1.7 ##STR54## 4.17 (1H, s, C3 proton), 5.3 - 5.6 (2H, m, β-lactam protons), 5.87 (1H, d, α-proton), 7.1 - 7.5 (5H, m, aromatics), 8.5 (1H, s, pyrimidine proton), 9.2 - 10.0 (2H, 2 × d, 2 × NH); λmax (0.3% NaHCO3 solution) 206 (ε = 25,800), 230 (ε = 12,140) and 300 n.m. (ε = 11,000).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[O:7]=[C:8]([NH:33][C:34]1[C:35]([I:53])=[C:36]([C:50]([NH2:52])=[O:51])[C:37]([I:49])=[C:38]([C:41]([NH:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47])=[O:42])[C:39]=1[I:40])[CH2:9][C:10]([NH:12][C:13]1[C:14]([I:32])=[C:15]([C:29]([NH2:31])=[O:30])[C:16]([I:28])=[C:17]([C:20]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])=[O:21])[C:18]=1[I:19])=[O:11].Cl.[OH-].[Na+].[Cl-].[Cl-].[Ca+2:59].O.[Cl:61][CH2:62][CH:63]([OH:66])[CH2:64][OH:65].O>O.C(O)(=O)C>[Cl-:1].[Cl-:61].[Ca+2:59].[Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[O:11]=[C:10]([N:12]([C:13]1[C:14]([I:32])=[C:15]([C:29]([NH2:31])=[O:30])[C:16]([I:28])=[C:17]([C:20]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])=[O:21])[C:18]=1[I:19])[CH2:62][CH:63]([OH:66])[CH2:64][OH:65])[CH2:9][C:8]([N:33]([C:34]1[C:35]([I:53])=[C:36]([C:50]([NH2:52])=[O:51])[C:37]([I:49])=[C:38]([C:41]([NH:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47])=[O:42])[C:39]=1[I:40])[CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:7]
Reactant: NC(=O)c1c(I)c(NC(=O)CC(=O)Nc2c(I)c(C(N)=O)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Cl
Agent: OCC(O)CCl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N(CC(O)CO)C(=O)CC(=O)N(CC(O)CO)c2c(I)c(C(N)=O)c(I)c(C(=O)NCC(O)CO)c2I)c1I
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A CaCl2 solution was prepared by dissolving CaCl2.2H2O (233 kg) in water (723 kg). A 3-chloro-1,2-propanediol (CPD) solution was prepared by dissolving 3-chloro-1,2-propanediol (176 kg) in water (176 kg). The 4000 L glass-lined reactor was charged with water (907 kg) and 5,5′-[(1,3-dioxo-1,3-propanediyl)diimino]bis[N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide] (563 kg). The pH of the slurry was adjusted to 5.5 to 7.0 with 37% HCl or 30% NaOH as needed. 50% NaOH solution (128 kg) was charged to the reaction mixture while maintaining its temperature to ≦30° C. The CaCl2/water solution and then the CPD/water solution were each charged to the reaction mixture. The reaction mixture was then heated at 50° C. and stirred for ≈6 hours. 50% NaOH was added as needed to maintain the pH of the reaction at ≈10. When the reaction was complete, acetic acid (28 kg) was added to adjust the pH of the reaction mixture to 5. Using a jacket temperature of 75° C., water (1682 kg) was distilled off under vacuum. While cooling to 10° C., ethanol (2585 kg) was added to the residue in the reaction vessel. After stirring at 10° C. for 2 hours, the crude solid was collected by filtration. The solids were washed with ethanol (500 kg). The crude solid was dried at 55° C. under vacuum to give 783 kg of crude 5,5′-[(1,3-dioxo-1,3-propanediyl)bis[(2,3-dihydroxypropyl)imino]]bis[N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide]. The crude product contained 55% w/w 5,5′-[(1,3-dioxo-1,3-propanediyl)bis[(2,3-dihydroxypropyl)imino]]bis[N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide] which had a chromatographic purity of 77 area %.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:34]3[S:33][C:32]4=[C:31]([C:50]([C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[O:51])[N:30]=[C:29]([S:28][CH3:27])[N:36]4[CH:35]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CSc1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 94.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.78 g) was prepared in the same manner as in step a) of Example 1, except that 1.10 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.88 g of 5-methylthio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:17])([F:16])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>C(O)(=O)C>[F:3][C:4]([F:16])([F:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:1])=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)ccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Bromine (2.33 ml, 2 eq.) in acetic acid (15 ml) was added dropwise to a stirred solution of N-(2,2,2-trifluoro- ethyl)-2-nitroaniline (4) (5.0g, 23 mmol) in acetic acid (50 ml), in an ice bath. After the bromine addition was completed, the i-ce bath was removed and the -reaction mixture was stirred at room temperature for 30 minutes and poured onto crushed ice. The resultant yellow-orange precipitate was collected by filtration, washed with H2O three times and air dried to give 6.0 g (88% yield) of N-(2,2,2,-trifluoroethyl)-4-bromo-2-nitroaniline (5): mp 118°-120° C.; MS m/e 298 (M+), 1HNMR (DMSO-d6) δ4.33 (m, 2H), 7.28 (d, 1H, J=9.0 Hz), 7.72 (dd, 1H, J=2.2 Hz, 9.0 Hz), 8.18 (d, 1H, J=2.1 Hz), 8.31 (1H, -NH).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:15][O:14][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:13]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (10.0 g, 48.5 mmol) in DCM (80 mL) was added EtSH (16 mL) under ice-water bath. The mixture was stirred at 0° C. for 20 min before AlCl3 (19.5 g, 0.15 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated, and the aqueous phase was extracted with DCM (50 mL×3). The combined organic layers were washed with H2O, brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H), 5.56 (s, 1H), 3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[C:15](=[O:21])[CH2:16][CH2:17][C:18]=2[O:19][CH3:20])=[C:9]([CH3:22])[CH:8]=1>O1CCCC1.[Br-].[Zn+2].[Br-].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]>[CH3:3][C:2]1[CH:1]=[C:7]([C:12]#[C:11][CH3:13])[CH:8]=[C:9]([CH3:22])[C:10]=1[C:14]1[C:15](=[O:21])[CH2:16][CH2:17][C:18]=1[O:19][CH3:20]
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Reactant: CC#C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC#Cc1cc(C)c(C2=C(OC)CCC2=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of anhydrous zinc bromide (1.41 g, 6.3 mmol) in anhydrous tetrahydrofuran (8.0 ml) under nitrogen at 0°C., is added propynylmagnesium bromide (15.7 ml, 6.3 mmol, 0.4 M solution in tetrahydrofuran) dropwise. The reaction mixture is then allowed to warm to room temperature and stir for 10 minutes, then cooled again to 0°C. To this mixture is then added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.102 g, 0.13 mmol), followed by a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (0.370 g, 1.25 mmol) in anhydrous tetrahydrofuran (4.0 ml). The reaction mixture is heated at reflux for 4.5 hours, then allowed to cool to room temperature followed by quenching with saturated aqueous ammonium chloride (10 ml). Ethyl acetate is added, and the mixture is filtered through a bed of diatomaceous earth and the phases separated. The aqueous phase is extracted again with ethyl acetate (×3) and combined organics are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue is purified by flash column chromatography (ethyl acetate and isohexane as eluant) to afford 2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(C(C)C)c(CCc2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-[2(E)-phenylethenyl]pyridine (Example 34) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.19 (m, 7 H), 6.86 (m, 2 H), 4.36 (d, J=5.5 Hz, 2 H), 3.44 (sept, J=6.6 Hz, 1 H), 3.35 (sept, J=6.6 Hz, 1 H), 2.58 (m, 4 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.19 (t, J =5.5 Hz, 1 H). FAB-MS: calculated for (C26H30FNO) 391, found 392 (M+H). Anal. Calcd for C26H30FNO: C, 79.76; H, 7.72; N, 3.58. Found: C, 79.57; H, 7.61; N, 3.44. mp 158-159° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[C:13]([F:23])[C:12]=3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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)C>[F:23][C:13]1[C:12]2[C:11](=[O:24])[N:10]([C:6]3[C:7]([CH:8]=[O:9])=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([N:48]6[CH2:53][CH2:52][N:51]([CH:54]7[CH2:55][O:56][CH2:57]7)[CH2:50][C@@H:49]6[CH3:58])=[CH:44][N:43]=5)[C:27](=[O:59])[N:26]([CH3:25])[CH:31]=4)[CH:3]=[CH:4][N:5]=3)[CH2:22][CH2:21][C:20]=2[N:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18]2
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(c(F)c3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 95 °C
Yield: 214.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 134c (70 mg, 0.20 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 191j (192 mg, 0.40 mmol), Pd(dppf)Cl2 (33 mg, 0.040 mmol), potassium acetate (39 mg, 0.40 mmol), K3PO4 (87 mg, 0.40 mmol), acetonitrile (7 mL), and water (6 drops). After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 50:1 ethyl acetate/methanol to afford 237a (286 mg, purity: 46%, yield: 98%) as a solid. MS-ESI: [M+H]+ 667.3