Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH:16](Br)[CH3:17].Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[CH2:17][CH2:16][N:9]2[C:8]3[CH:13]=[CH:14][C:5]([CH2:3][OH:4])=[CH:6][C:7]=3[N:11]=[C:10]12
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Reactant: CC(Br)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1ccc2c(c1)nc1n2CCS1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
To a round bottomed flask was added 2.83 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 2.55 grams of dibromoethane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1 M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and cocentrate yielded 2.04 grams (60%) product. MS: 207.0 (M+H). H-NMR(DMSO): □ 7.34(m, 2H), 7.08 (m, 1H), 5.15(m, 1H, OH), 4.53 (m, 2H, CH2), 4.34 (m, 2H, CH2), 4.00 (m, 2H, CH2).
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])OC.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].COC>CO>[CH3:7][O:6][P:2]([CH3:1])([CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])=[O:5]
Reactant: C=CC(=O)OCC
Reactant: COP(C)(=O)OC
Agent: COC
Solvent: CO
Product: CCOC(=O)CCP(C)(=O)OC
Temperature: 60 °C
Yield: 97.9 %

Procedure:
A flask filled with nitrogen and fitted with a cooling trap is charged with 216 g of dimethyl methanephosphonate; the contents are heated to 60° C. and a mixture of 200 g of ethyl acrylate and 100 g of methanol is added dropwise in the course of 1 hour, the temperature rising to 65° C. The reaction mixture is further stirred for 1 hour, during which period a total of 91 g of dimethyl ether are collected in the cooling trap. Excess methanol is removed by vacuum distillation. The crude product is obtained in a yield of 362 g with a 97.3% purity, which corresponds to a theoretical yield of 97.9%. The boiling point of a sample is 100°-102° C. at 0.013 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[C@H:17]([CH3:18])[CH2:16][O:15][C:14]2=[O:19])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[C@H:17]([CH3:18])[CH2:16][O:15][C:14]2=[O:19])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.6 %

Procedure:
To a mixture of methyl 4-bromo-2-methoxybenzoate (5.8 mL), (R)-4-methyloxazolidin-2-one (2 g) described in Preparation Example 25, potassium carbonate (2.8 g) and copper (I) iodide (760 mg) were added toluene (10 mL) and N,N′-dimethylethylenediamine (880 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g). Methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), 1N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N hydrochloric acid (16 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (2.2 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.N12CCN(CC1)CC2>CC#N>[N:27]1[CH:26]2[NH:30][CH:31]=[CH:32][CH:25]2[C:24]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[S:11])=[CH:3][C:2]=2[F:1])=[N:29][CH:28]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Clc1ncnc2[nH]ccc12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(OC2=NC=NC3NC=CC23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a mixture 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (11 mg, 0.075 mmol, commercially available) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified reverse phase preparative HPLC to give the title compound (5.3 mg, 16%) as a white solid. 1H NMR (CDCl3) δ 12.46 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.95 (dd, 1H, J=11.6, 2.8 Hz), 7.43 (m, 1H), 7.34 (m, 1H), 7.29 (m, 4H), 7.13 (app. T, 2H, J=8.6 Hz), 6.80 (s, 1H), 3.72 (s, 2H); MS(ESI+) m/z 440 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[NH2:28][C:27]1[CH:29]=[CH:30][N:23]([C:19]2[CH:20]=[CH:21][C:16]([N:14]3[CH:15]=[C:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[N:12]=[N:13]3)=[CH:17][CH:18]=2)[C:24](=[O:25])[N:26]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1ccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c(=O)n1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.23 mmol), cytosine (100 mg, 0.90 mmol), CuI (23 mg, 0.12 mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol), potassium carbonate (96 mg, 0.69 mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C18H14ClN7O2S (M+H)+ 428.1, 430.1 (Cl pattern).
Reaction SMILES: O=O.[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].S(=O)(=O)(O)[OH:14]>C(O)(=O)C>[CH3:10][C:9]1[C:8](=[O:14])[CH:7]=[C:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 40 °C
Yield: 1567.4 %

Procedure:
Oxygen was passed into a solution of 0.68 g (2 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene in 150 ml of 85% by weight aqueous acetic acid and, during this, a solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol and 0.5 g of concentrated sulfuric acid in 75 ml of 85% by weight acetic acid was added dropwise while stirring vigorously at 40° C. After oxygen uptake ceased, the mixture was subjected to a steam distillation. The distillate was extracted with tert-butyl methyl ether. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to dryness to yield 12.0 g (80%) of 2,3,5-trimethylbenzoquinone in the form of yellow oily crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([O:16][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[O:7][CH:6]=1)=[O:4].I([O-])(=O)(=O)=O.[Na+].B.[Na].Cl.S([O-])(O)=O.[Na+].[Cl-].[Na+]>O.CCOCC>[CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([OH:16])[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2C(CO)=CC[C@H]12
Agent: B
Agent: Cl
Agent: O=S([O-])O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
First, 100 g of geniposide was dissolved in 650 ml of water. After 115 g of sodium periodate was added to the solution, the reaction mixture was stirred at room temperature for two hours. After 41 g of sodium boron hydride was further added, the reaction mixture was further stirred at room temperature for two hours. Subsequently, a 6N aqueous hydrochloric acid solution and ether were added, the reaction mixture was stirred at room temperature for four hours. After the addition of sodium hydrogen sulfite and sodium chloride, the reaction mixture was stirred to thereby separate an ether layer. After the ether layer was separated and dried, ether was distilled off, and a yellow solid was obtained. The solid was further recrystallized from methanol and ether to yield 43 g of genipin.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15].[Cl-].[NH4+]>CN(C=O)C.O>[CH3:15][N:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccnc2[nH]ccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(C=O)ccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (0.252 g, 1.72 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added sodium hydride (45.5 mg, 1.90 mmol). After 5 min, iodomethane (0.13 mL, 2.1 mmol) was added. After 30 min, the reaction was treated with saturated aqueous ammonium chloride, diluted with water, and extracted 2× with dichloromethane. The combined organic solution was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes to provide 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 161.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6](Br)[CH:5]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([CH:10]=[O:11])[CH:9]=1)=[O:21]
Reactant: COC(=O)c1cc(Br)c(OCc2ccccc2)c(C=O)c1
Reactant: COc1ccc(F)cc1B(O)O
Product: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(F)ccc2OC)c1
Yield: 58 %

Procedure:
Proceeding as in Reference 19, but substituting 4-benzyloxy-3-bromo-5-formyl-benzoic acid methyl ester (1.0 g, 2.71 mmol) and 5-fluoro-2-methoxyphenyl boronic acid (0.691 g, 4.16 mmol), gave 6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acid methyl ester (0.620 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)=[O:31]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:20])[C:17]([O:19][CH2:29][C:30](=[O:31])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)C1(NC(=O)OCc2ccccc2)COC1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C(=O)OCC(=O)c1ccc(C(F)(F)F)cc1)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
2-(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)propanoic acid (Preparation 28, 1.5 g, 5.37 mmol) and triethylamine (1.12 mL, 8.06 mmol) were stirred in ethyl acetate (50 mL). 2-Bromo-1-[4-(trifluoromethyl)phenyl]ethanone (1.51 g, 5.64 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (2.19 g, 88%).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][CH:27]([OH:42])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH3:15]>CC(C)=O.O>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][C:27](=[O:42])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:30]=3)[CH2:24][CH2:25]2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(C2(CC(O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(C2(CC(=O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Jones reagent (2 ml, prepared by the method described in Fieser and Fieser Vol. 1, p. 142) is added dropwise to a stirring solution of 1-(4-ethoxyphenyl)-1-(3-(3-phenoxyphenyl)-2-hydroxypropyl)-cyclopropane (0.25 g) in acetone (5 ml) whilst maintaining the temperature below 5° C. After 15 min. the mixture is allowed to warm up to room temperature over 4 h, diluted with water, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The product is purified by thin layer chromatography on silica gel diluted with 15% diethyl ether in petroleum ether (b.p. 60°-80° C.). Yield 0.03 g, nD 1.5580.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(C)CBr
Yield: 106.5 %

Procedure:
The olefins 66 can also be prepared by reacting the corresponding substituted phenols with ethyl 4-bromo-3-methyl-2-butenate in the presence of potassium carbonate and small amount of 18-crown-ether in methylene chloride. The starting material ethyl 4-bromo-3-methylbutenate has been obtained from the reaction of ethyl 3,3-dimethylacrylate with N-bromosuccinimide (NBS) as follows: to 20 g of ethyl 3,3-dimethylacrylate in 250 ml of carbon tetrachloride, 30 g of N-bromosuccinimide (NBS) and 0.01 g of azobisisobutyronitrile were added. The mixture was refluxed for 3 hours. Succinimide was removed by filtration and the filtrate was washed with chloroform. The combined organic layers were washed sequentially with saturated sodium sulfite, saturated sodium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 34.4 g ethyl 4-bromo-3-methyl-2-butenate (Safaryn, J. E.; Chiarello, J.; Chen, K. M.; Joullie, M. M.; Tetrahedron, 1986, 42, 2635). The product can be further purified by silica gel flash column chromatography using ether/hexane (e.g. 1:50) as eluent, and hydrolyzed to the corresponding carboxylic acid with aqueous methanolic NaOH. ##STR12## wherein R1 =H, CF3, R or OR;
Reaction SMILES: [CH3:1][C:2]12[CH2:26][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:28])([CH3:27])[CH2:3]2.[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:31][N:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]([N:7]2[CH2:8][C:2]3([CH3:1])[CH2:26][CH:6]2[CH2:5][C:4]([CH3:28])([CH3:27])[CH2:3]3)=[O:10])=[CH:12][CH:13]=1)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CI
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)c3ccccc3)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-benzamide (500 mg, 1.33 mmol) in dry THF (40 ml) was added sodium hydride (64 mg, 1.594 mmol in 60% mineral oil) and the mixture was stirred for 30 min. Methyl iodide (99 μl, 1.594 mmol) was added and the stirring was continued for an additional 2 hrs. The volatiles were evaporated in vacuo and the residue was purified by column chromatography (silica gel) using EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording 300 mg (58%) of the title compound as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[O:26]C2CCCCO2)[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.O1CCCC1.[CH3:38][SH:39].[Na]>C(O)C>[OH:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][S:39][CH3:38])[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1
Reactant: COc1ccc(OC2CCCCO2)c(C2(CCCCBr)Sc3ccccc3N(C)C2=O)c1
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(O)c(C2(CCCCSC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-(4-bromobutyl)-2-[5-methoxy-2-(tetrahydropyran-2-yloxy)phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (4.9 g, compound No. 34) in ethanol (25 ml), 20-25% aqueous sodium methyl mercaptan solution (16.6 ml) is added. Ethanol (15 ml) and tetrahydrofuran (20 ml) are added to the mixture. The mixture is stirred for 45 minutes at room temperature, and concentrated in vacuo. 2N Hydrochloric acid (50 ml), tetrahydrofuran (25 ml) and ethanol (25 ml) are added to the residue dissolved in tetrahydrofuran (50 ml), and the mixture is stirred for 45 minutes at room temperature. The reaction mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 3.0 g (77.3%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH:50](O)[CH2:51][CH2:52][CH2:53][CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:50]([C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[F:42])[CH2:51][CH2:52][CH2:53][CH3:54])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCCC(O)c1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At 0° C., 4-chlorobenzenethiol (435 mg, 3.00 mmol), triphenylphosphine (798 mg, 3.00 mmol), and diisopropyl azodicarboxylate (588 μl, 3.00 mmol) were successively added to a solution of 1-(2,5-difluorophenyl)-1-pentanol (300 mg, 1.50 mmol) in methylene chloride (6 ml). The reaction mixture was stirred at room temperature for 15 hours, diluted with methylene chloride, and then washed successively with a 1N aqueous solution of sodium hydroxide and brine. After drying over MgSO4, the mixture was concentrated. The residue thus obtained was purified twice by medium-pressure chromatography on a silica gel column (first time with 1% ethyl acetate-hexane, and second time with hexane), whereby the title compound (266 mg, 54%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH:10](=[N:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CN=Cc1ccccc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 33.61 gms of glycine t-butyl ester and 27.19 gms of benzaldehyde in 215 ml benzene was added 21.5 gms of magnesium sulfate in one portion with stirring at room temperature. The reaction was stirred 18 hours at room temperature, filtered, diluted with ether and washed with saturated sodium bicarbonate and brine. The ether solution was then dried over magnesium sulfate, concentrated and distilled to yield 48.41 gms (86%) of t-butyl N-benzylideneglycinate.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml cyclopropanecarbonyl chloride (0.2 mmol). After 1.5 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 82 mg white solid (98%). MS (ISP) 519.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][NH:4][C:5]1=[N:6][C:7](=[O:24])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:27].C(OCC)(=O)C>>[ClH:27].[ClH:27].[OH:1][C:2]([CH3:26])([CH3:25])[CH2:3][NH:4][C:5]1=[N:6][C:7](=[O:24])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCNCC1

Procedure:
A mixed solution of tert-butyl 4-[(Z)-{4-[(2-hydroxy-2-methylpropyl)amino]-2-oxo-1,3-thiazol-5(2H)-ylidene}methyl]piperidine-1-carboxylate (1.93 g) and 4M hydrogen chloride/ethyl acetate solution (20 mL) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give the title compound (1.70 g).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:18](=[O:19])[CH2:17][C:16]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Yield: 53.4 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol), ethyl hydrogen malonate (0.25 g, 1.87 mmol) in methylene chloride (20.0 mL) was added EDCI (0.36 g, 1.87 mmol) and HOBt (0.25 g, 1.87 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 3-(3-(2-tert-butylphenoxy)azetidin-1-yl)-3-oxopropanoate (0.29 g, 53%) as a colorless oil.