Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][C:7]=2[CH:16]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:29])C.Cl>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][C:7]3[CH:16]=[C:3]([CH:2]=[O:29])[CH:4]=[CH:5][C:6]=3[O:15][C:10]=12
Reactant: ClCc1ccc2c(c1)Cc1cccnc1O2
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1ccc2c(c1)Cc1cccnc1O2

Procedure:
A mixture of 52 g of 7-chloromethyl-5H-[1]benzopyrano[2,3-b]pyridine, 63 g of hexamethylenetetramine, 160 ml of water and 160 ml of acetic acid is stirred under reflux for 3 hours. To the reaction mixture is added 80 ml of concentrated hydrochloric acid, and the whole mixture is refluxed for 20 minutes, then diluted with 200 ml of water, and cooled. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from dioxane to give 5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde melting at 171°-173°C.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15].O>CS(C)=O>[O:2]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=CCCCCC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of sodium bicarbonate (0.250 g), potassium iodide (0.050 g), and 6-bromo-N-[4-(trifluoromethyl)phenyl]hexanamide (1.00 g) in dimethylsulfoxide (15 mL) was heated at 125°-130° C. for 3.5 hours while stirring under a nitrogen atmosphere. The reaction was treated with water (75 mL) and extracted with ether. The ether extract was washed with brine (50 mL), dried over sodium sulfate after adding dichloromethane (30 mL), filtered, and concentrated in vacuo. Chromatography using 50/50 ethyl acetate/hexane gave a white solid (Rf 32 0.2 in same solvent system, 0.326 g), identified as the title compound. m.p.: 129.5°-131.0° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[Br-].[CH2:25]([Zn+])[CH:26]([CH3:28])[CH3:27].C1COCC1>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.C1(C)C=CC=CC=1>[CH2:25]([C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (0.5 g, 1.3 mmol), Pd(PPh3)2Cl2 (140.3 mg, 0.20 mmol) and toluene (8 mL) under N2. To the above was injected a 2 M solution of isobutylzinc(II) bromide in THF (10.4 mL, 5.2 mmol). The resulting mixture was stirred under N2 at 20° C. for 0.5 h then 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.30 g (64%) of tert-butyl 4-(5-isobutyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate as a yellow solid. MS m/z: 361 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH3:14][C:11]1([CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([C:21](=[O:22])[C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:31])([F:32])[F:15])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN2CCC(C(=O)c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (80 mg, 0.37 mmol), 4-(4-trifluoromethylbenzoyl)piperidine (95 mg, 0.37 mmol), sodium acetate (150 mg, 1.83 mmol) and DMF (2 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, washed with a saturated saline solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 2-methyl-6-nitro-2-[4-(4-trifluoromethylbenzoyl)piperidin-1-yl]methyl-2,3-dihydroimidazo[2,1-b]oxazole (46 mg, yield 29%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Cl)cc1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Cl)CCC1

Procedure:
using isopropyl 2-bromo-4-chloro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2-bromo-4-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 131°-132° C.
Reaction SMILES: [F:1][C:2]1[C:13]([I:14])=[CH:12][C:5]([CH2:6]OS(C)(=O)=O)=[C:4]([CH2:15]OS(C)(=O)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30]1([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH:36]([N:43]1[CH2:15][C:4]2[C:5](=[CH:12][C:13]([I:14])=[C:2]([F:1])[CH:3]=2)[CH2:6]1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a mixture of 5.93 mmol methanesulfonic acid 4-fluoro-5-iodo-2-methanesulfonyloxymethyl-benzyl ester and 14.8 mmol N,N-diisopropylethylamine in 7 ml DMF at 0° C. was added dropwise a solution of 6.53 mmol diphenylmethylamine in 5 ml DMF. The mixture was heated at 60° C. for 16 h and was then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a light yellow solid (55% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].I[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:20]
Reactant: CC(C)I
Reactant: CCCCC(=O)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCCCC(=O)C(c1ccccc1)C(C)C
Temperature: 0 °C

Procedure:
To an ice-cold magnetically stirred mixture of 1-phenylhexan-2-one (Intermediate II-1) (7.04 gram, 0.04 mol) and sodium methoxide (4.32 g, 0.08 mol) was added dropwise 2-iodopropane (15 ml) in a nitrogen atmosphere. The resulting mixture was heated for 1 hour at reflux temperature. The obtained mixture was allowed to attain room temperature and concentrated. The resulting residue was taken up in diethyl ether and water. The diethyl ether layer was separated and successively washed with an aqueous Na2S2O3 solution and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was further purified using Sepacore equipment: (petroleum ether/diethyl ether=19/1 (v/v)) to give 2-methyl-3-phenyl-octan-4-one (Intermediate IIa-1) (3.52 gram) as a colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.66 (d, J=7, 3H), 0.81 (t, J=7, 3H), 0.96 (d, J=7, 3H), 1.10-1.24 (m, 2H), 1.36-1.54 (m, 2H), 2.29-2.47 (m, 3H), 3.30 (d, J=10 Hz, 1H), 7.20-7.33 (m, 5H). Rf (petroleum ether/diethyl ether=98/2 (v/v))˜0.25.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12>>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1)[C:12]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3ccc(O)c(Cl)c3)[C@H]2SC1
Yield: 77.3 %

Procedure:
2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (1 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g.).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][O:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:14]=1.C(N(CC)CC)C>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:13]([O:12][CH3:11])=[N:14]2)=[CH:27][CH:26]=1
Reactant: COc1nn(-c2ccc(O)cc2)c2ncccc12
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nn(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc12
Temperature: 160 °C
Reaction time: 7 h
Yield: 13.2 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.23 g), 4-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (0.24 g) and triethylamine (1.0 ml) was stirred under a nitrogen atmosphere at 160° C. for 7 hr. The reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture. The precipitated solid was filtered off, silica gel was added to the filtrate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). Then, it was purified by HPLC(C18) (mobile phase: water/acetonitrile (0.1% TFA-containing eluents)) to give the title compound (0.047 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([N:15]([CH2:18]C)[CH2:16][CH3:17])C>>[CH3:18][N:15]([CH3:13])[C@@H:16]1[CH2:17][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:1][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
This titled amide was prepared from the trans-diamine and 4-nitrobenzoylchloride according to general procedure B using p-nitrobenzoylchloride (1.86 g.; 0.01 mole), the diamine (1.42 g.; 0.01 mole) and triethylamine (1.01 g.; 0.01 mole). The crude oil was crystallized from ether-petroleum ether (30°-60°); 2.232 g. (77% yield) of yellow needles, m.p. 103°-104°. The analytical sample melted at 102°-103°. uv sh 215 nm (ε 2,000); λmax 266 (11,800). ir NH 3380, 3320; N-alkyl 2780; C=O 1645; C=C 1605, 1595; amide II/NO2 /C=C 1535, 1525, 1485, 1350; aromatic 870, 845, 720, nmr in CDCl3 and 100 MHz was in accord. Mass spectrum M+ 291.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.[CH2:23](O)[CH2:24][OH:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:25][CH2:24][CH2:23][O:22]3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(c1cccc(C2(c3ccccc3)OCCO2)c1)c1nc(N)no1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.20 g, 4.09 mmol) in toluene (10 ml) were added ethylene glycol (0.80 g, 12.9 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.15 mmol). After reflux for 10 h, the mixture was cooled at room temperature and extracted with toluene. The extracts were washed with aqueous sodium hydrogen carbonate and then water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole (1.06 g, 77% yield) as crystalline material: mp 112.0°-113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1cccs1
Reactant: CCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCOc1cccs1
Temperature: 25 °C

Procedure:
A mixture of 2-methoxythiophene (5.13 g, 44.93 mmol), n-C11H23OH (15.5 g, 89.87 mmol), toluene (50 mL), and p-toluenesulfonic acid monohydrate (0.85 g, 4.47 mmol) was heated to reflux under nitrogen for 19 hours. After cooling to room temperature, the reaction mixture was poured into water (150 mL), and the mixture was extracted with dichloromethane (DCM, 250 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash column on silica gel with hexane as eluent (slowly up to a hexane:DCM (8:2, v/v) mixture), leading to a colorless oil as the product (7.76 g, 67.9%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14](I)=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:33][CH2:32]1>O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH:32]=[CH2:33])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: C1COCCO1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(C)c(Br)c2OC)c2ncnc(N)c12
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (12 mg, 0.017 mmol) was added to a mixture of vinyl boronic acid MIDA (110 mg, 0.6 mmol, from Aldrich, item #704415), 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 0.57 mmol) and sodium carbonate (0.14 g, 1.1 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction was degassed with N2 3 times. The reaction was stirred at 95° C. for 4 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography eluting with CH2Cl2/EtOAc (max. EtOAc 60%). LCMS calculated for C17H18BrClN5O (M+H)+: m/z=422.0; Found: 422.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:31]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:31])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-indazole (35 mg, 0.083 mmol) and sodium cyanoborohydride (10.4 mg, 0.166 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (42%). 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.29 (s, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.98 (s, 3H), 3.44 (s, 2H), 2.50 (m, 2H), 2.00-2.25 (m, 7H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.2, 160.2, 139.4, 133.9, 128.62, 128.56, 124.8, 124.6 (q, J=272 Hz), 124.5 (q, J=2.9 Hz), 122.6 (q, J=33 Hz), 121.1, 119.7 (q, J=4.8 Hz), 115.0, 114.9, 78.7, 70.5, 51.8, 46.2, 40.2, 38.3, 32.6. Mass spec.: 436.15 (MH)+. Accurate mass spec.: m/z 436.2008 [MH]+, Δ=0.9 ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[CH2:16]([SH:19])[CH2:17][SH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[S:18]1[C:12]2([CH2:13][CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[CH2:10][CH2:11]2)[S:19][CH2:16][CH2:17]1
Reactant: SCCS
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCC3(CC2)SCCS3)c(O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). To the stirred solution was added ethane-1,2-dithiol (0.49 ml) and a few crystals of p-toluenesulfonic acid monohydrate and the reaction mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution (20 ml) was added, and the layers were separated. The aqueous layer was diluted with water (40 ml) and extracted into ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (1.34 g, 98%) as a white solid. δH (CD3OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m), 2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m), 6.85 (1H, d); m/z (ES+) 283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
2,5-dihydroxyacetophenone (5.00 g, 0.0329 mol), benzyl bromide (3.72 ml, 0.031 mol), potassium carbonate (4.31 g, 0.031 mol) and acetone (150 ml) were added to a 500 ml round bottom flask. The reaction mixture was heated overnight at reflux and then was cooled to ambient temperature. When cool, deionized water (150 ml) was added to the reaction mixture and the reaction mixture was extracted three times with 100 ml portions of diethyl ether. The combined ether layers were dried with sodium sulfate and concentrated in vacuo yielding a dark solid. This dark solid was recrystallized from 50:50 (ethanol:water) yielding 3.09 g of 2-hydroxy-5-benzyloxyacetophenone as yellow needles.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][C:20]1([CH3:32])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[O:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:19][C:20]1([CH3:32])[C:24]([CH3:25])([CH3:26])[O:23][B:22]([C:27]2[CH:31]=[N:30][N:29]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH:28]=2)[O:21]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A mixture of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (7.33 g, 26.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.09 g, 26.2 mmol), and Cs2CO3 (12.8 g, 39.3 mmol) in DMF (50 mL) was heated at 100° C. for 24 h. The mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with water (3×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (20 to 40% ethyl acetate:hexanes) to afford 3.84 g (39%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.74 (s, 1H), 4.17-4.35 (m, 3H), 2.89 (m, J=11.12 Hz, 2H), 2.14 (d, J=14.65 Hz, 2H), 1.90 (qd, J=12.25, 4.42 Hz, 3H), 1.48 (s, 9H), 1.33 (s, 12H); MS (ESI): 379.15 [M+H]+; HPLC tR=3.17 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To 1 g (3.7 mmol) of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester were added successively 554 μL (4.08 mmol) of 4-methoxybenzyl chloride, 565 mg (4.08 mmol) of potassium carbonate and 37 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then 250 mL of water were added and a white precipitated solid was collected by filtration. This crude material was back washed with diethyl ether and dried under reduced pressure yielding 1.15 g (79%) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid.