Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+]([C:6]1[CH:11]=C[C:9]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)([O-])=O.C1(O)CCCC1.O>O1CCCC1>[CH:9]1([O:12][C:13]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:19][CH2:20]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:11]1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 6 mg, 0.15 mmol) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (Example 123; 37 mg, 0.078 mmol) in anhydrous tetrahydrofuran (750 μL) under argon. Cyclopentanol (70 μL, 0.77 mmol) was added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered, evaporated, and purified on an Isco 4 g column, eluting with 0-4% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (6 mg, 18%). Mass spectrum (ES) MH+=423.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:22]=1[CH:27]=[O:28]
Reactant: O=Cc1ncccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ncccc1-c1cccnc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 3-tributylstannanyl-pyridine (255 mg, 0.693 mmol), 3-Bromo-pyridine-2-carbaldehyde (123 mg, 0.660 mmol), and Pd(PPh3)4 (53.1 mg, 0.046 mmol) in toluene (4 mL) was heated to 90° C. for 23 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30, then 0:100) afforded [3,3′]Bipyridinyl-2-carbaldehyde (35 mg, 29%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20].N#N>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc2cc[nH]c2c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)COc1ccc2cc[nH]c2c1

Procedure:
6-Hydroxyindole (1.0 g, 7.51 mmol) in degassed MeCN (10 mL) was added K2CO3 (1.14 g, 8.26 mmol) followed by tert-butyl bromoacetate (1.16 g, 8.26 mmol) and the reaction mixture was stirred for 20 hous under N2. The precipitate was filtered off and the solvent was removed in vacuo to give (1-H-indole-6-yloxy)-acetic acid. This was converted to [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid tert-butyl ester follwing general procedure (A). [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid was obtained by treating the intermediate with TFA-DCM (1:1) (2 mL) for 90 min before the solvent was removed in vacuo.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15](=[S:16])[C:14]4[CH:17]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[CH:20][C:13]=4[O:12][C:11]3=[O:25])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)(Cl)Cl.C(N(C(C)C)CC)(C)C.[PH:40](=[O:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C.CN(C)C1C=CN=CC=1>[P:40]([O:21][C:19]1[C:18]([CH:22]([CH3:23])[CH3:24])=[CH:17][C:14]2[C:15](=[S:16])[N:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)[C:11](=[O:25])[O:12][C:13]=2[CH:20]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1O
Reactant: O=[PH](OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc2c(=S)n(-c3ccc4c(c3)CCC4)c(=O)oc2cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
To a stirred solution of 0.30 g (0.84 mmols) of 5 in 10 mL of anhydrous acetonitrile at 5° C., was added 0.4 mL (4.24 mmols) of CCl4, 0.31 mL (1.78 mmols) of diisopropylethylamine and 10 mg (85□mols) of 4-dimethylaminopyridine in that order. After stirring the mixture for 5 min. at 5° C., 0.34 mL (1.27 mmols) of dibenzyl phosphonate 6 was added drop wise and the mixture stirred for 1 h at 5° C. The reaction was quenched with water, extracted the product with ethyl acetate and organic layers were washed with water and brine. Filtration of the product through a plug of silica gel afforded 0.52 g of the product 7 as brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5](Cl)=[O:6].[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)Cl)ccc1N1CCCN(C)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCN(C)CC1

Procedure:
489 mg (1.61 mmol) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl amine is added dropwise with stirring. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1). The fractions evaporated down are treated with ethereal hydrochloric acid, after total concentration evaporated twice with ethyl acetate and diethyl ether and dried i. vac. at 70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:12][O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)[CH:3]=1
Reactant: COc1cc(Br)cn2nccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnn(C)c2)cn2nccc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1375 mg, 6.61 mmol), tetrakis(triphenylphosphine)palladium (0) (254 mg, 0.220 mmol), and sodium carbonate (700 mg, 6.61 mmol) were suspended in a mixture of 1,4-dioxane (19.8 ml) and water (2.2 ml). The mixture was sparged with argon for 10 minutes, then heated to 90° C. After 2 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid contaminated with trace amounts of triphenylphosphine oxide. Analytically pure material could be obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(C(Br)C([O-])=O)C1C=CC=CC=1.Br[CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>C(#N)C.O>[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCOCCNCCOCCO
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])C(Br)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOCCN(CCOCCO)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIPEA (0.23 mL, 2.0 eq.) was added to a solution of 18 (0.19 g, 1.0 eq.) in dry acetonitrile (1.5 mL) at 0° C. Benzylbromoacetate (0.11 mL, 1.0 eq.) was added in one portion and the reaction was allowed to warm to room temperature and stir for 18 hrs. A further portion of benzyl bromoacetate (55 μL) was added and the reaction was stirred for a further 2 h. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (3×20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL) before being dried (MgSO4), filtered and concentrated at reduced pressure to yield give a colourless oil (0.40 g). The crude product was purified by silica column chromatography eluting with 3% methanolic ammonia in DCM to give 0.23 g (79%) of 19 as a colourless oil. 13C NMR (CDCl3) δ 171.3, 156.2, 135.7, 128.6, 128.4, 79.0, 72.3, 70.2, 69.4, 69.2, 66.2, 61.9, 55.2, 54.2, 40.5, 28.5. ESMS (C22H36N2O7) [M+H]+ calc. 441.2601. found 441.2596.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][NH2:14].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=O.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][NH:14][CH2:18][CH2:17][CH:16]([CH3:20])[CH3:15]
Reactant: COc1cccc2c(CN)cccc12
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2c(CNCCC(C)C)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methoxynaphthalen-1-ylmethylamine (Preparation 12) (389 mg, 2.08 mmol) in MeOH (15 mL), was added 3-methylbutyraldehyde (223 μL, 2.08 mmol). The mixture was stirred for 16 h at rt under nitrogen before adding NaBH4 (236 mg, 6.24 mmol). After stirring for 1 h water (0.5 mL) was added and the solvent removed in vacuo. The mixture was partitioned between EtOAc (100 mL) and NaHCO3 (25 mL), the organic phase was washed with water (25 mL), brine (25 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (DCM: MeOH: NH4OH, 97:3:0.3 to 95:5:0.5) to give the title compound: RT=2.46 min; m/z (ES+)=258.1 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 99 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (off-white solid) in 99% yield. HRMS calc for [C39H34ClFN2O6S2−H] 743.1458 found 743.14511.
Reaction SMILES: [I-].[CH2:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[N+:24]=1C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:28](C1C=CC=CC=1C=O)[CH2:29]CCCCCCCCCC.C1(CCCCCCCC[Mg]Br)C=CC=CC=1.COC1C=CC=CC=1C1OCC(C)(C)N=1>O1CCCC1>[C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][CH2:22][C:23]([CH3:26])([CH3:27])[N:24]=2)[CH:11]=[CH:12][CH:13]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Reactant: CCCCCCCCCCCCc1ccccc1C1=[N+](C)C(C)(C)CO1
Agent: Br[Mg]CCCCCCCCc1ccccc1
Agent: COc1ccccc1C1=NC(C)(C)CO1
Agent: [I-]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 8-phenyloctylmagnesium bromide (from 24.25 mmoles of 8-phenyloctyl bromide and 21.27 mmoles of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmoles) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmoles) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmoles). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][C:16](Br)=[O:17].O>ClCCl>[Br:14][CH2:15][C:16]([NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(N)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC(=O)CBr)on1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
3-Methyl-isoxazol-5-ylamine (2.9 g) and potassium carbonate (9.8 g) were suspended in dichloromethane (100 mL) at room temperature and 2-bromoacetyl bromide (6 g) was added dropwise. The mixture was allowed to stir overnight. Water (0.3 mL) was added together with a further quantity of potassium carbonate (3 g) and the reaction mixture stirred for a further 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated in vacuo. The crude product was purifed by column chromatography on silica eluting with ethyl acetate/isohexane (50:50) to give sub-titled compound (4.8 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>CCCCCC.C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:13]([OH:18])=[O:17]
Reactant: CC(C)C(=O)O
Reactant: BrCCCCOCCc1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCCOCCc1ccc(N2CCOCC2)cc1)C(=O)O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
n-Butyllithium in hexane (1.53M, 113.5 ml) was added dropwise to N,N-diisopropylamine (17.9 g) in THF (100 ml) at -78° under nitrogen. The mixture was warmed to 0°, stirred for 1 h and treated dropwise with isobutyric acid (7.65 g) in THF (20 ml). The resulting suspension was stirred at room temperature for 3 h, and the product of stage (ii) (20.0 g) was added dropwise. The reaction mixture was stirred for 16 h at room temperature and the solvent was evaporated. The resultant oil was partitioned between EA (250 ml) and water (250 ml). The aqueous layer was acidified to pH 6 with 2N aqueous hydrochloric acid and the organic extract was separated. The aqueous layer was extracted with EA (250 ml) and the combined extracts were concentrated to leave the title compound as an orange oil (20.4 g). T.l.c. (ER) Rf 0.53.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl>[O:20]=[C:19]([N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:1])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (113 mg, 0.35 mmol) in dichloromethane (4 ml) in a sarstedt tube was treated in one portion with solid 1,1′-carbonyldiimidazole (60 mg, 0.37 mmol). This mixture was shaken at room temperature for 30 minutes. Pyrrolidine (34 mg, 0.48 mmol) in dichloromethane (2 ml) was then added and the shaking continued for 16 hour at room temperature. The reaction mixture was washed with a mix of saturated sodium bicarbonate solution (4 ml) and brine (2 ml). The organic layer was then added to a 2 g SCX column and eluted with ethyl acetate (25 ml), the solvent removed under reduced pressure and the residue purified by mass directed auto-prep to give the title compound as a yellow oil (30 mg, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:14][C:12](=[O:13])[CH:10]([O:11][CH:39]([O:40][CH2:41][CH3:37])[CH3:38])[CH:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 409 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3-phenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25° C. for 1.5 h. The mixture was diluted with 80 mL of hexane and ethyl acetate and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase was dried over sodium sulfate and concentrated to give 235 mg (70%) of 2-tertbutoxy-4-phenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:14]([CH2:24][CH3:25])[CH:13]=1)#[N:11]>CO>[CH2:24]([C:14]1[CH:13]=[C:12]([C:10](=[NH:11])[NH:8][OH:9])[CH:17]=[C:16]([CH3:18])[C:15]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:25]
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)O
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Yield: 81.1 %

Procedure:
Potassium tert-butoxide (2.71 g, 24.1 mmol) was carefully dissolved in MeOH (25 mL). To this solution hydroxylamine hydrochloride (1.44 g, 20.7 mmol) followed by 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (1.50 g, 6.90 mmol) dissolved in MeOH (7.5 mL) was added. The mixture was refluxed for 8 h and the solvent was evaporated. The residue was dissolved in 2 N aq. HCl and extracted with EA. The pH of the aq. phase was adjusted to pH 5 by adding sat. aq. NaHCO3 and the mixture was extracted three times with EA. The combined org. extracts were dried over Na2SO4, filtered, evaporated and dried to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid as a white solid (1.4 g). LC-MS: tR=0.60 min, [M+1]+=251.17.
Reaction SMILES: C[C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].C1(=O)O[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH:18]1[CH:17]=[CH:16][C:12]([C:13]([C:7]2[CH:6]=[CH:5][C:3]([OH:4])=[CH:2][C:8]=2[OH:9])=[O:14])=[CH:11][CH:19]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(O)cc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Under an argon atmosphere, 2-methylresorcinol (10.0 g, 80.6 mmol) and phthalic anhydride (11.2 g, 75.6 mmol) were combined in dry nitrobenzene (250 mL). The mixture was cooled to 0° C. and aluminum(III) chloride (23.5 g, 176 mmol) was added in one portion. The resulting dark olive slurry was allowed to warm to room temperature and stirred for an additional 16 h under argon. The reaction was poured into a vigorously stirring mixture of hexanes (300 mL) and 1 M HCl (1 L). The precipitate was filtered and recrystallized twice from methanol/water to afford benzophenone 1 as a beige powder (16.0 g, 78% yield). 1H NMR (CD3OD, 500 MHz): δ 8.05 (1 H, dd, J1=8.0 Hz, J2=1.0 Hz), 7.62 (2 H, dt, J1=33.0 Hz, J2=9.0 Hz), 7.33 (1 H, d, J=7.5 Hz), 6.74 (1 H, d, J=8.5 Hz), 6.20 (1 H, d, J=8.5 Hz), 2.05 (3 H, s). HRMS (ESI) calcd for [M−H]− 271.0601, found 271.0601.