Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[Br-].[B:23](OC)([O:26]C)[O:24]C>O1CCCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[B:23]([OH:26])[OH:24]
Reactant: COB(OC)OC
Reactant: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(C(F)(F)F)ccc1Oc1ccc(F)cc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a suspension of magnesium (0.083 g, 3.42 mmol) in tetrahydrofuran (1.000 mL) was added 0.5 mL of a solution of example 34a (1.099 g, 3.11 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was warmed (about 40-50° C.) until reaction commenced. The remaining solution of starting bromide was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The resulting Grignard solution was added dropwise to a solution of trimethyl borate (0.696 mL, 6.23 mmol) in tetrahydrofuran (1.5 mL) at 0° C. The reaction mixture was stirred at ambient temperature. After 1 hour at ambient temperature, the reaction mixture was quenched with ice water and then neutralized with 2 M HCl. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes) to provide the title compound (0.650 g, 65.7% yield).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]5[CH2:20][CH2:19]5)[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)nc1N
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: [C:1]([C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:14][CH2:15][CH:16]=[C:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[OH-:30].[Na+].[BH4-].[Na+].[OH-]>O.O1CCCC1>[C:1]([C:4]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:14][CH2:15][CH2:16][C:17]([OH:30])([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, 8-acetyl-8-phenyl-12-methyl-11-heptadecenoic acid (4.8 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M solution hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 8-acetyl-8-phenyl-12-hydroxy-12-methyl-heptadecanoic acid as a yellow viscous oil which is purified by chromatrography on silica gel with 4% methanol in chloroform as eluant.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C1(C2[O:17]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:17]
Reactant: CSc1ncccn1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncccn1

Procedure:
The methylsulfanyl-pyrimidine compound of formula (83) is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature. The product of formula (84), a methanesulfinyl-pyrimidine derivative, is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (84) may, however, be additionally purified by means of chromatography or recrystallisation.
Reaction SMILES: [C:1]([CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>CO.C(O)(=O)C>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[S:11])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(CC(=S)N1CCC[C@H]1C(=O)O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=S)CC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
N-(2-Benzoylthioacetyl)-L-proline obtained in Example 16, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minutes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain N-(2-benzoylthioacetyl)-L-proline methyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[C:24]1([C@@H:30]([NH2:39])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@@H:30]([NH:39][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 81 %

Procedure:
The title compound was prepared in a yield of 81% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and (S)-1-phenyl-2-(4-methylphenyl)ethylamine.
Reaction SMILES: C1COCC1.O.[N:7]([CH2:10][C:11]1([C:23]([F:26])([F:25])[F:24])[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:22])[O:12]1)=[N+]=[N-].P(OC)(OC)OC>C(OCC)(=O)C>[ClH:21].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[NH:14][C:13](=[O:22])[O:12][C:11]([CH2:10][NH2:7])([C:23]([F:25])([F:26])[F:24])[C:16]=2[CH:17]=1
Reactant: [N-]=[N+]=NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: COP(OC)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cl
Product: NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a mixed solution of THF (20 mL) and water (10 mL) containing 4-(azidomethyl)-6-chloro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.59 g, 8.44 mmol), trimethyl phosphite (2 mL, 16.9 mmol) was added at room temperature, and the reaction solution was stirred at 60° C. for 5 hours. After the reaction solution was left to cool, water was added thereto, and the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. To the residue, a 4 N hydrochloric acid-dioxane solution (30 mL) was added, and the mixture was stirred at 40° C. for 24 hours. After the mixture was left to cool, the resulting solid was collected by filtration and washed with ethyl acetate and then dried under reduced pressure, whereby the objective compound (2.31 g, 86%) was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:28]2([CH3:27])[CH2:30][CH2:29]2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CC1(CO)CC1
Product: CC1(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)CC1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 1-methylcyclopropanmethanol (76.3 mg; 0.841 mmol), example 49 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCN2CCCCC2)cc1
Yield: 118.7 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-nitrobenzene (2.01 g, 0.01 mol), piperidine (2.55 g, 0.03 mol), and toluene (10 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate evaporated to give 2.97 g of 1-[2-(1-piperidinyl)ethoxy]-4-nitrobenzene as an orange oil, MS M+ (m/e) 251.18. This material (1.25 g, 0.004 mol) was hydrogenated in ethanol (25 mL) in the presence of 10% Pd-C catalyst at 40 psig and 25° C. overnight. Filtration and evaporation of the reaction mixture gave 0.95 g of 4-[2-(1-piperidinyl)ethoxy]aniline as a light brown oil, MS M+ (m/e) 221.24. A solution of this oil (0.220 g, 1.0 mmol), 3-methyl-5,8-dimethoxy-2-tetralone (6, 0.206, 0.94 mmol), and 1,2-dichloroethane (3.5 mL) was treated with sodium triacetoxyborohydride (0.300 g, 1.4 mmol) and acetic acid (0.060 g, 1.0 mmol) and the resulting mixture was stirred overnight at 25° C. The reaction was treated with 3N sodium hydroxide solution with vigorous stirring. The organic layer was separated, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered and evaporated to a red oil. This material was purified by C-18 reverse phase high pressure liquid chromatography affording compound 60 as a pink solid. 1H NMR (300 MHz, CDCl3): δ 7.10–7.22 (m, 2H), 6.52–6.82 (m, 4H), 4.25–4.33 (m, 2H), 3.60–3.80 (m, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.48–3.38 (m, 2H), 2.80–3.05 (m, 4H), 1.80–2.10 (m, 4H), 1.10–1.50 (m, 3H), 1.00 (d, 3H). MS M+ (m/e) 425.38.
Reaction SMILES: [Cl:1][C:2]1[C:11](/[CH:12]=C/C2C=CC=CC=2)=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1.CSC.CN(C=[O:28])C>CO>[Cl:1][C:2]1[C:11]([CH:12]=[O:28])=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Cl)c(/C=C/c3ccccc3)nc2N1
Reactant: CN(C)C=O
Solvent: CSC
Solvent: CO
Product: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
7-Chloro-6-((E)-styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (8.0 g, 27.9 mmole) was dissolved in a mixture of DMF (400 mL) and methanol (40 mL), and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring for 45 minutes, then the excess ozone was removed by bubbling oxygen through the solution for 30 min. Dimethylsulfide (21 mL, 279 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2O (150 mL). The collected solid was washed with additional Et2O and dried to afford a white solid (4 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CCCCCC.C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH:31]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:32]
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhdyrous tetrahydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithiumhexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13]C(=O)N[C:10]2=[O:15])=[C:5]([S:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=1)#N.[OH-:25].[Na+].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>>[NH2:13][CH:9]([C:6]1[CH:7]=[CH:8][C:29]([C:28]([OH:31])=[O:30])=[CH:4][C:5]=1[S:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:10]([OH:15])=[O:25]
Reactant: [OH-]
Reactant: N#Cc1ccc(C2NC(=O)NC2=O)c(SCCc2ccccc2)c1
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Product: NC(C(=O)O)c1ccc(C(=O)O)cc1SCCc1ccccc1

Procedure:
A stirred solution of 5-(4-cyano-2-(2-phenylethylthio)phenyl)hydantoin (1.20 g, 3.56 mmol) in 2M sodium hydroxide (10 ml, 20 mmol) was heated under reflux for 72 hours. The cooled solution was acidified with 5M hydrochloric acid (2 ml, 20 mmol), then with acetic acid (1 ml) to pH~4. The pale solid was filtered (0.9 g), washed with CHCl3 (10 ml) and redissolved in water (10 ml) and 0.880 ammonia solution (0.1 ml). The solution was acidified with acetic acid (0.4 ml) to precipitate a fine solid that was filtered and washed with methanol to give the title product as an off-white solid, m.p. 227°-231° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10]C)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:13][S:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:30])[CH2:27][O:28][CH3:29])=[CH:20][CH:19]=1>CCOCC>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[OH:30][CH:26]([CH2:27][O:28][CH3:29])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][S+:14]([CH3:1])[CH3:13])=[CH:19][CH:20]=1
Reactant: COCC(O)COc1ccc(OCCSC)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: COCC(O)COc1ccc(OCC[S+](C)C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A 6 g quantity of methyl p-toluenesulfonate was added to 2.72 g of 2-{4-(2-hydroxy-3-methoxypropoxy)phenoxy}ethyl methyl sulfide. The mixture was stirred at room temperature for 12 hours. Ether was added to the reaction mixture and the insoluble solid was separated and recrystallized from ethanol-ether, giving 4.15 g of 2-{4-(2-hydroxy-3-methoxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate in 90.4% yield, M.P. 88° to 91° C.
Reaction SMILES: [H-].[Na+].[C@@H:3]1([OH:9])[CH2:7][CH2:6][CH2:5][C@H:4]1[OH:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>CN(C=O)C.CCOCC>[Br:10][C:11]1[N:12]=[C:13]([CH2:17][O:8][C@@H:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[OH:9])[CH:14]=[CH:15][CH:16]=1
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O[C@@H]1CCC[C@H]1OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 mg, 11.96 mmol) was suspended in DMF (12.0 mL) and cooled to 0° C. (1R,2R)-Cyclopentane-1,2-diol (1.22 g, 11.96 mmol) was added and the reaction was stirred for 30 minutes. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.30 g, 1.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was then diluted with ether and quenched with water. After layer separation, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]([C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[CH3:25])([CH3:20])([CH3:19])[CH3:18].CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[C:17]([O:21][C:22](=[O:33])[NH:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([N:13]2[CH2:12][CH:11]([O:10][C:9]3[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:7][CH:8]=3)[CH2:14]2)=[CH:30][CH:31]=1)[CH3:25])([CH3:18])([CH3:19])[CH3:20]
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 0.9 g (4.1 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1), 1.2 g (4.1 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (I.3), 1.6 g (16.4 mmol) NaOtBu, 0.49 g (1.64 mmol) 2-(di-tert-butylphosphino)biphenyl and 0.38 g (0.41 mmol) tris-(dibenzylideneacetone)-dipalladium(0) are added under an argon atmosphere 25 mL 1,4-dioxane. The mixture is stirred for 12 h at 45° C. The mixture is filtered, washed with MeOH and concentrated. The residue is purified by HPLC (silica gel; PE/ethyl acetate; gradient 9:1→1:1) to yield the desired product.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=O)=O.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: CS(=O)(=O)OCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1cccc(C(F)(F)F)c1
Yield: 98.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.68 g of 3-trifluoromethylbenzyl methanesulfonate and 2.00 g of indole-4-carbaldehyde to give 4.12 g of 1-(3-trifluoromethylbenzyl) indole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 99%.
Reaction SMILES: C(O[CH2:10][CH2:11][CH2:12][CH:13]([CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][NH:15][S:16]([CH2:19][CH2:20][CH2:21][Cl:22])(=[O:18])=[O:17])(=O)C1C=CC=CC=1.C[O-].[Na+].ClCCCS(NCC(CC(O)C)COC(=O)NCCCCCCCCCCCCCCCCCC)(=O)=[O:49]>CO>[Cl:22][CH2:21][CH2:20][CH2:19][S:16]([NH:15][CH2:14][CH:13]([CH2:12][CH:11]([OH:49])[CH3:10])[CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)O
Reactant: CCCCCCCCCCCCCCCCSCC(CCCOC(=O)c1ccccc1)CNS(=O)(=O)CCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)O
Yield: 54.5 %

Procedure:
A mixture of 1.24 g (2.0 mM) of 2-(benzoyloxypropan-1-yl)-1-(3-chloropropylsulfonylamino)-3-n-hexadecylthiopropane ml4 and 0.77 ml (2 mM) of 5.18 M/L sodium methoxide in methanol solution in 50 ml of methanol is allowed to react by the same procedure as described in (131) and 562 mg (54.5% yield) of the titled compound ml5 is obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:36]([OH:38])=O.O[NH:47][C:48]([C:50]1[C:51]2[CH:52]=[CH:53][N:54]=[CH:55][C:56]=2[CH:57]=[CH:58][CH:59]=1)=[NH:49]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:36]2[O:38][N:49]=[C:48]([C:50]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:51]=3[CH:52]=[CH:53][N:54]=[CH:55]4)[N:47]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
A microwave vial was charged with HATU (2.5 g, 6.57 mmol), triethylamine (1.48 ml, 10.7 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 1.15 g, 5.34 mmol) and N-hydroxy-5-isoquinolinecarboximidamide (D1; 1 g, 5.34 mmol). The solution was stirred at room temperature for 30 minutes. The reaction vessel was sealed and heated under microwave irradiation at 130° C. for 120 min. After cooling, the reaction mixture was filtered. The isolated grey-brown solid was washed with acetonitrile before being dried in vacuo at 60° C. to give the title compound as a grey solid (738 mg, 37%).
Reaction SMILES: [S:1](=[O:3])=[O:2].[C:4]([C:8]1[CH:9]=[C:10](N)[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:7])([CH3:6])[CH3:5].N([O-])=O.[Na+].[ClH:20]>C(O)(=O)C.O.[Cu]Cl>[C:4]([C:8]1[CH:9]=[C:10]([S:1]([Cl:20])(=[O:3])=[O:2])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cc(N)ccc1Cl
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
Amounts used: 10 mL of acetic acid was saturated with sulfur dioxide, 220 mg of copper(I) chloride, 1.5 g (8.20 mmol) of 3-tert-butyl-4-chloro-phenylamine dissolved in a mixture of 3 mL of acetic acid and 3 mL of concentrated hydrochloric acid, 0.622 g of sodium nitrite in 3 mL of water. Flash chromatography on silica using 0-15% ethyl acetate in hexanes afforded 0.42 g of the product as a white solid. LC-MSD spectrum not observed.