Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[N:15]=[C:14]([CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:10]2[CH:11]=[CH:3][C:4]([C:5]([Cl:38])=[O:6])=[CH:8][CH:9]=2)=[CH:13][C:14]([CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[O:28][C:27]([CH3:33])([CH3:34])[CH2:26]2)=[N:15]1
Reactant: CCc1cc(-c2cc(C3CC(C)(C)OC(C)(C)C3)nn2-c2ccccc2OC)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-benzoic acid (Example 46) (177 mg, 0.41 mmol) in 4 mL of DCM was added oxalyl chloride (0.043 mL, 0.49 mmol) and 1 drop of DMF and the mixture stirred for 3 hrs at RT The mixture was concentrated and used without further purification in the next step.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24].[OH-].[Na+].Cl>C(O)CCC.O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:24][C:23]1[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCC(CCOc1ccc(O)cc1)C(F)(F)F
Temperature: 130 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
0.39 g of the above-obtained 3-trifluorometylheptyl p-toluenesulfonate and 0.25 g of hydroquinone were dissolved in 1 ml of butanol. To the solution was added a solution of 0.07 g of sodium hydroxide in 2 ml of butanol, followed by 5 hours of stirring at 130° C. for reaction. Then, water and 1N-hydrochloric acid were added to the reaction solution, followed by extraction with diethyl ether. The ether solution was dried with sodium sulfate, and the solvent was distilled off. The product was then purified by thin layer chromatography with methylene as the developer to obtain 0.17 g (yield:54%) of p-(3trifluoromethylheptyloxy)phenol which showed: [α]D26 -2.8, [α]43526 -4.9 (c 1, methylene chloride).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:11].OO>>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cl
Reactant: O=C(O)c1cccnc1O
Agent: OO
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 1.5 h
Yield: 32.2 %

Procedure:
To a solution of 42.5 g (0.3 mole) of 2-hydroxynicotinic acid in 212.5 ml of 37% hydrochloric acid (0.3 mole) was added dropwise 46 ml of a 30% aqueous solution of hydrogen peroxide (0.45 mole) at 25°±3° C. using an ice bath to control the temperature over a 10 minute period. The mixture was seeded with crystals from a previous trial. After 5-10 min. some crystals developed and after 1.5 hr precipitate was collected and rinsed three times with water and dried to give 16.75 g (Fraction 1) (32% yield) of crude 5-chloro-2-hydroxynicotinic acid containing 5-7% starting 2-hydroxynicotinic acid and some 3,5-dichloro-2-hydroxypyridine. After about 4 hr total time from the start, an additional 23 ml of 30% hydrogen peroxide was added to the mother liquor at 25°-30° C. At the 5th hour another 23 ml (0.22 mole) of 30% hydrogen peroxide was added. The solid was then collected and rinsed with water and dried to give 3.77 g (Fraction 2) (7.6% of yield) of crude 5-chloro-2-nicotinic acid containing 10-20% 3,5-dichloro-2-hydroxypyridine and a trace of starting material. The mother liquor was stirred overnight. No new precipitate was present. The mother liquor was then combined with rinsings from Fractions 1 and 2 and the resulting solution was extracted 3 times with methylene chloride. The combined methylene chloride layers were back washed with water, dried and evaporated to give 5.5 g of solid (Fraction 3). Analysis of Fraction 3 by 1HNMR gave many signals. Chemical Ionization Mass Spectroscopy analysis showed compounds m/e 214, 216, 218, 220 corresponding to compounds with multiple (2-3) halogen atoms on pyridine ring. For the trial as a whole, the total yield of 5-chloro-2-hydroxynicotinic acid was about 35% of theory considering the impurities and yield of polychlorinated impurities was about 10% on a theoretical mole base.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:7][C:5]=2[N:6]=1.O.NN>CCO>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2o1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2cc(CN)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of 2-((2-methylbenzo[d]oxazol-5-yl)methyl)isoindoline-1,3-dione (200 mg; 0.68 mmol), and hydrazine monohydrate (715 mg; 21.89 mmol) in EtOH (30 ml) was refluxed, under nitrogen, for 4 h. After cooling to rt, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure affording (2-methylbenzo[d]oxazol-5-yl)methanamine as an orange oil. LC-MS (conditions D): tR=0.50 min.; [M+H]+: 163.07 g/mol.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[OH:13][C@@H:14]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:31]2[C:30](=[O:36])[CH2:29][C@@:28]2([CH3:37])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:27])[CH:25]=[CH2:26])[CH2:15]1>C(O)C.O>[C:6]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:26][CH2:25][C:24](=[O:27])[C@@H:23]1[C@:28]2([CH3:37])[C@H:20]([C@H:19]3[C@H:31]([C:30](=[O:36])[CH2:29]2)[C@:32]2([CH3:35])[C@H:16]([CH2:15][C@H:14]([OH:13])[CH2:34][CH2:33]2)[CH2:17][CH2:18]3)[CH2:21][CH2:22]1)(=[O:8])[CH3:7]
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(=O)C(CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium ethoxide, prepared from 120 mg of sodium in ethanol (20 ml), was treated with acetylacetone (1 ml) and the resulting solution added to a solution of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) in ethanol (20 ml). The mixture was stirred at room temperature for 1 hour, poured into water, and extracted into ether. The extract was washed with water, dried (Na2SO4) and evaporated to a white foam which was purified by preparative t.l.c. (ethyl acetate/petrol) to give title compound (480 mg) as a white foam [α]D + 79.5 °(c, 0.59).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([CH2:32]Br)=[CH:27][C:26]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:26]([Cl:34])=[CH:27][C:28]([CH2:32][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:29][C:30]=1[Cl:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2cc(Cl)c(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-5-bromomethyl-1,3-dichloro-benzene (CAB02118, 1.73 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (78%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (1 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (47.08 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silca gel chromatography (5% MeOH/95% CHCl3) yielding 67% (94 mg, 0.163 mmol) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])=[C:9]([F:25])[CH:8]=1.[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1.C(N(CCCC)CCCC)CCC>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]2[C:20]([OH:21])=[N:27][C:28]3[N:29]([N:30]=[CH:31][N:32]=3)[C:15]=2[OH:16])=[C:9]([F:25])[CH:8]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(CCCCN(C)C)cc1F
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)CCCCc1cc(F)c(-c2c(O)nc3ncnn3c2O)c(F)c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of diethyl 2-{4-[4-(dimethylamino)butyl]-2,6-difluorophenyl]malonate (1.0 g, 2.7 mmol), 3-amino-1,2,4-triazole (250 mg, 3.0 mmol), and tributylamine (0.71 mL, 3.0 mmol) is stirred under nitrogen atmosphere at 160° C. for 16 h and cooled to room temperature. The mixture is stirred with 20 ml of hexanes. The precipitates are collected by filtration, washed with hexanes to give 6-{4-[4-(dimethylamino)butyl]-2,6-difluorophenyl}[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol as a white solid (795 mg). MS: m/z 362.1 (M−H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][C:26](=[O:35])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([O:25][C:26](=[O:35])[NH:27][CH2:28][CH:29]1[CH2:30][CH2:31][N:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:33][CH2:34]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=[N+]([O-])c1cc2cccnc2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 23 %

Procedure:
To a solution of 7-chloro-6-nitro-quinoline (974 mg, 4.67 mmol) in N,N-dimethylformamide (25 mL) were added potassium carbonate (1.93 g, 14.01 mmol) and piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.00 g, 4.67 mmol) and the resulting mixture was heated at 100° C. overnight. The reaction mixture was cooled and partitioned between water (500 mL) and ethyl acetate (300 mL). The organic layer was separated, washed twice with water (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified twice by flash chromatography to afford 415 mg of [1-(6-nitro-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as an orange solid.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:13][CH3:14])[CH:5]([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH2:13]([C:4]([CH:5]([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCC(C)=CCC(C)C(=CCBr)CC
Reactant: Oc1ccc2c(c1)OCCC2
Product: CCC(C)=CCC(C)C(=CCOc1ccc2c(c1)OCCC2)CC

Procedure:
Following the procedure of Example 1, 1-bromo-3-ethyl-4,7-dimethyl-2,6-nonadiene and 7-hydroxy-chromane are reacted to form 7-(3-ethyl-4,7-dimethyl-2,6-nonadienyloxy)-chromane, nD20 = 1.5226.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:10][C:9]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 4-bromo-3-(trifluoromethy)aniline (360 mg, 1.50 mmol, 1 eq.) in DMF (5 mL) is added phenyl boronic acid (274 mg, 2.25 mmol, 1.5 eq.), K2CO3 (621 mg, 4.5 mmol, 3 eq.), and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol, 0.1 eq.). The mixture is purged with N2 (g) for 5 minutes and heated at 120° C. for 20 h. After cooling to room temperature, the reaction is diluted with EtOAc and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by gradient silica gel chromatography (hexanes to 3:1 hexanes/EtOAc) to give 2-trifluoromethyl-biphenyl-4-ylamine. [MS: (ES+) 238.1 (M+1)+].
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[C:17]([C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:15]=2[CH3:14])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: Cc1ccc(C(=O)N2N(C3CCCCC3)C(=O)C2(C)C)c(C)c1

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dimethylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: C1(COC(=O)[N:10]([C@@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)C=CC=CC=1.[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[CH:48][N:47]=[C:46]([N:52]3[CH2:58][C:57]4[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:56]=4[O:55][CH2:54][CH2:53]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]>>[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[CH:48][N:47]=[C:46]([N:52]3[CH2:58][C:57]4[CH:59]=[C:60]([C:27]5[CH:28]=[C:23]6[NH:22][C:21]([C@H:19]([NH2:10])[CH3:20])=[N:30][C:24]6=[N:25][CH:26]=5)[CH:61]=[CH:62][C:56]=4[O:55][CH2:54][CH2:53]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: C[C@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc5nc([C@@H](C)N)[nH]c5c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1R)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and {-4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.59 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.61 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 4.80 (m, 2H), 4.53 (m, 1H), 4.43 (m, 1H), 4.27 (m, 1H), 4.06 to 3.93 (m, 2H), 2.96 to 2.78 (m, 2H), 2.62 (m, 1H), 2.32 (m, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.67 (d, 3H), 1.41 (m, 2H), 1.16 (m, 1H), 0.99 (t, 3H); MS (EI) for C27H31N7O: 470 (MH+).
Reaction SMILES: C(=O)(OC1C=CC=C([N+]([O-])=O)C=1)OCC[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:29]=[CH:28][C:12]2[C:13]#[C:14][C:15]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=3[CH2:17][CH2:18][C:11]=2[CH:10]=1.CCN(CC)CC.[C:48]([NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH:64][C:65](=[O:79])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]1[C@@H:78]2[C@@H:73]([NH:74][C:75]([NH:77]2)=[O:76])[CH2:72][S:71]1)([O:50][C:51]([CH3:54])(C)C)=[O:49]>CN(C=O)C>[O:76]=[C:75]1[NH:74][CH:73]2[CH2:72][S:71][CH:70]([CH2:69][CH2:68][CH2:67][CH2:66][C:65]([NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:48](=[O:49])[O:50][CH2:51][CH2:54][O:5][CH2:6][CH2:7][O:8][C:9]3[CH:29]=[CH:28][C:12]4[C:13]#[C:14][C:15]5[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:16]=5[CH2:17][CH2:18][C:11]=4[CH:10]=3)=[O:79])[CH:78]2[NH:77]1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)Oc3cccc([N+](=O)[O-])c3)ccc1C#C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(=O)NCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)ccc1C#C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of carbonate 16 (0.15 g, 0.28 mmol) in DMF (approximately 2 mL) was added to a solution of Et3N (0.5 g, 4.95 mmol) and N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (Ning et al., Angew. Chem. Int. Ed. 2008, 47:2253-2255) (0.01 g, 0.28 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, most solvent was evaporated under reduced pressure, and the residue was separated by chromatography on (CH2Cl2:MeOH 30:1) to provide 0.164 g (0.21 mmol, 75%) of 6b. 1H NMR δ 7.19 (d, J=8.4 Hz, 2H), 6.88 (dd, J=9.5, 2.5 Hz, 2H), 6.76 (td, J=8.2, 2.5, 2H), 6.74-6.65 (m, 1H), 6.54 (s, b, 1H), 5.74 (s, b, 1H), 5.60 (s, b 1H), 4.49-4.43 (m, 1H), 4.29-4.22 (m, 3H), 4.16-4.10 (m, 2H), 3.97 (t, J=6.5, 2H), 3.87-3.81 (m, 2H), 3.76 (m, 2H), 3.59-3.48 (m, 7H), 3.42 (m, 2H), 3.37-3.12 (m, 2H), 3.21-3.09 (m, 4H), 2.86 (dd, J=12.6, 4.7 Hz, 1H), 2.72 (d, J=12.7, 1H), 2.42 (d, J=10.9, 2H), 2.21 (t, J=7.4, 2H), 1.81-1.56 (m, 5H), 1.48 (sex, J=7.4 Hz, 2H), 1.44-1.36 (m, 2H), 1.32 (t, J=7.4 Hz, 1H), 0.98 (t, J=7.4, 3H); 13C NMR δ 173.4, 164.1, 158.7, 158.1, 156.5, 154.8, 126.66, 126.63, 116.80, 116.72, 116.59, 115.8, 111.91, 111.83, 110.67, 110.14, 70.09, 70.04, 69.95, 69.90, 69.80, 69.54, 67.78, 67.52, 63.88, 61.80, 60.2, 55.6, 45.6, 40.8, 40.5, 39.1, 36.63, 36.61, 35.9, 31.3, 28.22, 28.08, 25.6, 19.2, 13.8, 8.5.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2)CC1
Yield: 34.2 %

Procedure:
The title compound (29 mg, 27%) was prepared as a white solid from {4-[(dimethylamino)carbonyl]phenyl}boronic acid (39 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.63-7.42 (m, 6H), 6.96 (d, 2H, J=8.8 Hz), 4.98-4.81 (m, 1H), 4.20 (bs, 2H), 3.84 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 3.04 (s, 3H), 2.84-2.74 (m, 2H), 2.08-1.92 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.14 (m, 8H); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([OH:13])=[O:12])=[O:6].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([OH:13])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NC(=O)CCCCl)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1Oc1ccccc1

Procedure:
The compound 3-(γ-chlorobutyrylamino)-4-phenoxy-5-sulfamylbenzoic acid (11.5 g) and anhydrous potassium carbonate (11.5 g) were slurried in dioxane (350 ml) and stirred under reflux overnight. The solvent was removed under reduced pressure and the residue taken up in a small volume of water. After acidification with 3N acqueous HC1, the product separated as a gum. Methylene chloride was added and the mixture stirred for 1 hour. The product 3-(2-oxo-1-pyrrolidinyl)-4-phenoxy-5-sulfamylbenzoic acid, now in the form of a powder, was filtered, washed with water, and air-dried to give 7.5 g (61% on two steps). A sample was recrystallized from aq. dioxane to give colorless crystals with m.p. 282°-285°; ir (Nujol) 3400, 3250, 2600 (broad), 1735, 1660, 1600, and 1575 cm-1 ; nmr (d6 -DMSO) 1.2-2.3 (m, 4H), 3.41 (t, J=6, 2H), 6.7-7.5 (m, C6H5), 7.65 (s, SO2NH2), 8.15 (d, J=2, CH), and 8.46 ppm (d, CH); mass spectrum m/e 283 (100%) and 376 (M+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+]>>[C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)OC
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1ccccc1
Reaction time: 15 h

Procedure:
α-Phenylmethylpropionate can be obtained under similar conditions, by reacting a mixture of phenylacetic acid, dimethyl carbonate and K2CO3, in a 1:20:2 molar ratio, in autoclave at a temperature of 225° C., for 15 hours.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H2O was added to the mixture and extracted with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give 967 mg (90%) of yellow armorphous. p 1H NMR (270 MHz, CDCl3) δ7.88 (1H, d, J=4.4 Hz), 7.66 (1H, d, J=4.0 Hz), 5.14 (1H, br. s).