Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCN=C1C1C=CC([NH:13][C:14]([C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:27])=[O:15])=CC=1.ClC1C=CC(NC(C2C3C(=CC=CC=3)CC(C(O)=O)N2)=O)=CC=1.[N:59]1([CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:64][CH2:63][CH2:62][CH2:61][C:60]1=[O:65].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[N:59]1([CH:66]2[CH2:71][CH2:70][N:69]([CH:18]3[C:19]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:25][CH:16]([C:14]([NH2:13])=[O:15])[N:17]3[C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[O:27])[CH2:68][CH2:67]2)[CH2:64][CH2:63][CH2:62][CH2:61][C:60]1=[O:65]
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: CN1CCN=C1c1ccc(NC(=O)[C@H]2Cc3ccccc3CN2C(=O)Nc2ccc(Cl)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1Cc2ccccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1Cc2ccccc2C(N2CCC(N3CCCCC3=O)CC2)N1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R) 2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (50 mg, 0.15 mmol), 4-(2-piperidinon-1-yl) piperidine (20 mg, 0.11 mmol) and triethylamine (30 uL, 0.22 mmol) in DMF (3 mL), BOP (70 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 30 min. It was then purified by HPLC to give the titled compound (31 mg). MS 495.2 and 497.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[N-:47]=[C:48]=[O:49].[K+]>O.C(O)(=O)C>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:48]([NH2:47])=[O:49])=[CH:3][C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)=[CH:5][N:6]=1
Reactant: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NC(N)=O
Yield: 53 %

Procedure:
To a suspension of (S)-2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (92 mg, 0.14 mmol) in water (0.75 mL) and acetic acid (1.2 mL) was added potassium isocyanate (20 mg, 0.25 mmol) according to the method described in Preparation 181. The residue was purified using SP1® Purification System (0% to 5% dichloromethane methanol) to obtain 61 mg (53% yield, 86% purity) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].O>O1CCCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of 1-bromo-3-fluorobenzene (10.0 g, 57.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (1.6M, 35.7 mL, 62.8 mmol) at −78° C. and the mixture was stirred at that temperature for 20 minutes. To the mixture was added 3-fluorobenzaldehyde (7.80 g, 62.8 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added water and the product was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 10.1 g of bis(3-fluorophenyl]methanol. To a solution of this compound (6.60 g, 3.0 mmol) in diisopropylether (50 mL) was added phosphorus tribromide (5.41 g, 20.0 mmol) with ice-cooling and the mixture was stirred at that temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropylether. The organic layer was washed with water and saturated with aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 5.61 g of the title compound. Yield 53%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.OC1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: C1CCNC1
Agent: CCN=C=NC(CCNC)NC
Agent: Oc1cccc2[nH]nnc12
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of meta-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.81 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 g of 1-(3-nitrobenzoyl)pyrrolidine, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-7-methyl-1-naphthalen-2-ylmethyl-1,3-dihydro-indol-2-one (495.7 mg, 1.36 mmol) in THF (30 ml) was added 4-picolyl chloride hydrochloride (893 mg, 5.45 mmol). The resulting suspension was purged with nitrogen gas for 10 minutes, after which time an aqueous potassium hydroxide (1N, 10.88 ml, degassed for 10 minutes prior to the addition) was added dropwise at room temperature. The dark solution was stirred at room temperature overnight. After removal of THF, the reaction mixture was partitioned between water and ethyl ether. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product. It was chromatographed on flash silica gel eluting with ethyl acetate to provide the title compound of 2D (524 mg, 0.956 mmol, 70.3% yield).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=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.[Cu]I>[CH3:26][C:22]1[N:21]=[C:20]([C:18]#[C:17][CH:16]=[C:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: Cc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
A mixture of Compound 1c (0.21 g, 0.86 mmol), 2-bromo-6-methylpyridine (0.11 mL, 0.95 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol), CuI (16 mg, 0.09 mmol) in anhydrous and degassed triethylamine (10 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 3.5:6.5) affording the title product (0.20 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@@H:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@@H:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Temperature: 81 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A mixture of (S)-tert-butyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (300 mg, 0.71 mmol, 1 equiv), 4-chloro-1-phenylbutan-1-one (130 mg, 0.71 mmol, 1 equiv), sodium iodide (42.6 mg, 0.28 mmol, 0.4 equiv), and potassium carbonate (196.3 mg, 1.42 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 10 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound as an oil (200 mg, 50%); MS for C35H41N3O4 m/z 568.4 (M+H)+.
Reaction SMILES: C([Li])CCC.C(S)CC.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C@@H:24]([C:48]3[CH:53]=[CH:52][C:51]([CH:54]4OCC[O:55]4)=[CH:50][CH:49]=3)[CH:25]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)C(N3[C@H]4CC5C(C)(C)[C@@]4(CC5)CS3(=O)=O)=O)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].Cl>C1COCC1>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C@@H:24]([C:48]3[CH:49]=[CH:50][C:51]([CH:54]=[O:55])=[CH:52][CH:53]=3)[CH2:25][C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc([C@@H](c2ccc(C3OCCO3)cc2)C(C(=O)N2[C@H]3CC4CC[C@@]3(CS2(=O)=O)C4(C)C)c2ccncc2)cc1OC1CCCC1
Agent: CCCS
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(C=O)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
n-Butyllithium (2.4M solution in hexane; 10.6 mL, 25 mmol) was added dropwise to a 0° C. solution of propanethiol (4.6 mL, 51 mmol) in THF (150 mL). After 15 minutes, (1R, 5S)-N-{(3R)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[4-(1,3-dioxolan-2-yl)phenyl]-2-(4-pyridyl)propanoyl}-10,10-dimethyl-3-thia-4-azatricyclo[5.2.1.01,5 ]decane-3,3-dioxide from Step 2 (9.7 g, 14.1 mmol) was added as a solid and the reaction mixture was stirred at room temperature for 3 days. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (80 mL) and water (40 mL). Sodium hydroxide (4.5 g, 113 mmol) was added and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with HCl 6N to pH 4.5 then heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and treated with NaOH 1N to pH 14 then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash-chromatography (silica gel, ether) to afford the title compound as a white foam (2.3 g, 41%). 1H NMR (400 MHz, CDCl3): δ 1.55 (m, 2H), 1.75 (m, 6H), 3.30 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.90 (d, 2H), 7.35 (d, 2H), 7.75 (d, 2H), 8.40 (d, 2H), 9.95 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.Cl>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]1[CH:18]=[C:13]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=2)[N:14]=[N:15][CH:16]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reaction time: 22.5 h
Yield: 95 %

Procedure:
1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (4.0 g, 0.024 mole), 3-chloro-5-methoxypyridazine (3.5 g, 0.024 mole), and 2,6-1-lutidine (3.0 g, 0.028 mole) were heated to reflux in toluene (75 mL) under N2 and held there for 22.5 h. The mixture was poured into diluted HCl (1%) aqueous solution and extracted 2×100 mL with ethyl acetate. The organic layer was extracted with brine followed by dilute NaOH (1%, 2×100 mL). The organic layer was dried (MgSO4), filtered through silica gel with ethyl acetate and evaporated in vacuo to give 5-methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-pyridazine (6.25 g, 95% yield) as a light brown solid. This solid was recrystallized from ethyl acetate/cyclohexane.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=4)=[CH:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][C:6]=3[N:10]=2)[C@H:12]([CH3:26])[CH2:13]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Bromo-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (152 mg, 0.3 mmol, Example 151) and 4-trifluoromethylphenylboronic acid (114 mg, 0.6 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:31])[F:32])[CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.9 %

Procedure:
To a mixture tert-butyl (3-tert-butyl-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.98 mmol, 1 equiv.), 3-(trifluoromethoxy)-phenylboronic acid (814 mg, 3.96 mmol, 2 equiv.) and copper acetate (541 mg, 2.97 mmol, 1.5 equiv.) in dichloromethane (30 mL) was added pyridine (315 mg, 0.315 mL, 3.96 mmol, 2 equiv.) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (3-tert-butyl-1-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)methylcarbamate (294 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][C:8]2[N:9]([CH3:12])[C:10](=[O:11])[C:4]3[CH:3]=[C:2]([CH2:24][CH:23]=[CH2:22])[CH:21]=[N:20][C:5]=3[N:6]([CH2:18][CH3:19])[C:7]=2[N:16]=1
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C)nc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(C)nc1N2CC
Temperature: 100 °C
Yield: 85.2 %

Procedure:
A solution of 8-bromo-5,11-dihydro-2,5-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (258 mg, 0.7 mmol) in DMF (7.4 mL) was degassed under reduced pressure for 20 min. Pd(PPh3)4 (43 mg, 0.04 mmol) was then added followed by allyltributyltin (0.3 mL, 0.85 mmol). After degassing under reduced pressure for 10 min, the mixture was heated to 100° C. for 1.5 h. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8:2) to give the title compound (184 mg, 98% yield) as a yellow solid.
Reaction SMILES: [S:1]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(N(CC)CC)C.[Na+:29].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([NH:38][C@@H:39]1[C:51](=[O:52])[N:41]2[C:42]([C:48]([O-:50])=[O:49])=[C:43]([CH2:46][OH:47])[CH2:44][S:45][C@H:40]12)=[O:37]>CN(C)C=O.O>[Na+:29].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([NH:38][C@@H:39]1[C:51](=[O:52])[N:41]2[C:42]([C:48]([O-:50])=[O:49])=[C:43]([CH2:46][O:47][C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[NH:11][S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:44][S:45][C@H:40]12)=[O:37]
Reactant: Cc1ccc(S(=O)(=O)N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccccc2C(=O)OCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cc4cccs4)[C@H]3SC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
In N,N-dimethylformamide (40 ml) is dissolved in 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.8 g), followed by the addition of N-tosylphthalimide (4.0 g) and triethylamine (2.0 ml) in that order. The mixture is stirred at room temperature for 4 hours. The reaction mixture is poured in water (100 ml) and rinsed with ethyl acetate. The aqueous layer is adjusted to pH 2.0 with dilute phosphoric acid and extracted with ethyl acetate. The extract is dried and, then, a solution of sodium 2-ethylhexanoate in isopropyl alcohol is added. By this procedure is obtained 7β-(2-thienylacetamido)-3-[2-(N-tosylcarbamoyl) benzoyloxy]methyl-3-cephem-4-carboxylic acid sodium salt (4.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:9]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1B(O)O)=[O:49]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:9]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH:48]=[O:49])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Yield: 65 %

Procedure:
To a solution of methyl 1-{2-[bis(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate in dioxane (0.15 M) were added 6 eq of Na2CO3 (2 M aqueous solution), 1.5 eq (2-formylphenyl)boronic acid and 0.2 eq of bis(triphenylphosphine)palladium(II) dichloride. The mixture was heated at reflux for 1.5 h. The reaction mixture was filtered and then the filtrate was diluted with EtOAc. The organic phase was washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge, 1.0:9.0 EtOAc/PE) to afford the title compound (65%). MS (ES+) m/z 663 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([Cu])#[N:11].N>CN1C(=O)CCC1>[NH2:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: Cc1cccc(Br)c1N
Agent: N
Solvent: CN1CCCC1=O
Product: Cc1cccc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-6-methylaniline (126 μL, 1 mmol) in dry NMP (3 mL) was added CuCN (197 mg, 2.2 mmol). The mixture was irradiated in a microwave at 220° C. for 40 minutes, cooled to room temperature and poured into a mixture of ammonia (50% w/v, 10 mL) and ice. The mixture was stirred for 30 min and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified on silica gel (50% EtOAc/hexanes) to yield a brown oil that crystallized on standing (128 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 2.08 (s, 3H), 5.68 (bs, 2H), 6.51-6.55 (t, 1H), 7.17-7.19 (d, 1H), 7.22-7.24 (dd, 1H). MS 133 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9-[3-(tetrahydro-3-furanyl)propyl]-9H-purin-6-amine (110 mg, 0.315 mmol) in methanol (9 ml) at room temperature was added 4M HCl in dioxane (1.89 ml). The pale yellow solution was stirred at room temperature for 18 hrs and then neutralised with 2M sodium hydroxide solution and evaporated to give a white solid. Trituration with water and filtration afforded the title compound as a cream solid (74 mg).