Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]4OCC[O:25]4)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=[O:25])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cc(C2OCCO2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Temperature: 40 °C
Reaction time: 7 h
Yield: 103.4 %

Procedure:
A solution 2-((3,4-dichlorophenyl)amino)-8-(1,3-dioxolan-2-yl)-6-nitroquinazolin-4-ol (1.08 g) in tetrahydrofuran (35 mL) and dimethylsulfoxide (1 mL) was treated with 10% (v/v) hydrochloric acid (25 mL). The resulting mixture was stirred at 40° C. for 7 h, then was cooled to room temperature and stirred for 16 h. Evaporation of the tetrahydrofuran in vacuo provided a brown slurry, from which the product was isolated by filtration. The brown solids were washed with water (50 mL) and dried. The crude product was dissolved in tetrahydrofuran (3.75 mL), dried over MgSO4, filtered and evaporated to afford the title compound (1.0 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 10.57 (s, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.54 (bd, J=2.1 Hz, 1H), 8.03 (bd, J=2.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.49 (dd, J=2.1, 8.7 Hz, 1H). HPLC Method A: 7.73 min. MS (APCI−): m/z 377, 379.
Reaction SMILES: ClC1C=C2C(=CC=1)C(O)=CC(C)=C2.BrC1C=CC(CC(=O)C)=CC=1.[Br:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([CH3:37])[CH:32]=[C:33]2[OH:36])=[CH:28][CH:27]=1.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=[O:40]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([CH3:37])[CH:32]=[C:33]2[OH:36])=[CH:28][CH:27]=1.[Br:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([CH3:37])[C:32]([CH:39]([OH:40])[C:38]([O:42][CH2:43][CH3:44])=[O:41])=[C:33]2[OH:36])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)Cc1ccc(Br)cc1
Agent: Cc1cc(O)c2cc(Br)ccc2c1
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1O
Reaction time: 0.33 h

Procedure:
7-Bromo-3-methylnaphthalen-1-ol was prepared in a similar manner as 6-chloro-3-methylnaphthalen-1-ol in Example 5 except using 1-(4-bromophenyl)propan-2-one instead of 1-(3-chlorophenyl)propan-2-one. To a solution of 7-bromo-3-methylnaphthalen-1-ol (11.5 g, 48.5 mmol) in dichloromethane (145 mL) at 0° C. was added a 1 M titanium(IV) chloride solution in dichloromethane (48.5 mL, 48.5 mmol) and stirred for 20 min. Ethyl glyoxylate (50% solution in PhCH3, 10.6 mL, 53.3 mmol) was added over 15 minutes and stirred for 1 hour at 0° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 14 hours. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, filtered, concentrated and purified by flash column chromatography (EtOAc/Hexanes) to provide the desired product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.52 (s, 1H), 8.34 (s, 1H), 7.49 (m, 2H), 7.13 (s, 1H), 5.67 (s, 1H), 4.24 (m, 1H), 4.16 (m, 1H), 2.29 (s, 3H), 1.23 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11]Br.[OH-].[Na+].C1(C)C=CC=CC=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:22]([N:29]1[CH2:11][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[CH:5]=2)[CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CBr)c(CBr)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CN(Cc1ccccc1)C2
Yield: 71.4 %

Procedure:
Combine in a round bottom flask 1,2-bis-bromomethyl-4-methoxy-benzene (1.0 g, 3.40 mmol), benzyltriethylammonium chloride (73.5 mg, 3.2 mmol), 50% NaOH (aq)/toluene (3.0 mL/14 mL), and then drop wise add benzylamine (0.37 mL, 3.39 mmol). Stir the reaction at room temperature for 3 hours, add to ethyl acetate, wash with water, brine, and dry over Na2SO4. After concentrating under reduced pressure, add the mixture to a 10 g SCX column, wash with MeOH, and elute with 1.0 N NH3-MeOH. Flash chromatograph using 3:1 hexanes:ethyl acetate to afford 580.0 mg, 2.42 mmol (71% yield) of the title compound as a brown oil: 1H NMR (500 MHz, CDCl3); 3.7 (3H, s), 3.9-4.0 (6H, m), 6.7-6.8 (2H, m), 7.1 (1H, d), 7.3-7.5 (5H, m); MS m/z 238 (M−1).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C(OCC)C>[Cl:8][C:9]1[C:10]([C:11]([C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[O:12])=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Brc1cccs1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2cccs2)c(Cl)n1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a diethyl ether suspension of magnesium was added dropwise 2-bromothiophene at room temperature, and the whole was reacted. After cooling to 0° C., the reaction mixture was added with 2-chloro-6-methylnicotinic acid and, after being warmed to room temperature, the whole was stirred for 12 hours. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine. NMR1: 7.79 (1H, dd, J=5.0, 1.1 Hz), 7.78 (1H, d, J=7.7 Hz), 2.63 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)cc1
Yield: 81 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 81%). 1H NMR (200 MHz, CDCl3): δ 3.16 (s, 4H), 3.78 (s, 3H), 4.16 (s, 4H), 6.88-6.93 (m, 4H), 7.27-7.80 (m, 4H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28])[CH:17]=1.C(N(CC)CC)C.CN(C=O)C>O>[C:32]([O:31][C:30]([NH:29][C@@H:27]([CH3:28])[CH2:26][O:25][C:18]1[CH:17]=[C:16]([S:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5])[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(=O)OC(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of 2-ethylhexyl 3-sulfanylpropanoate (2.17 g), tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (3.00 g), triethylamine (1.39 mL) and DMF (30 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.50 g). MS (ESI+): [M+H]+ 514.3.
Reaction SMILES: C(OO)(C)(C)C.[OH:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>[Mo](=O)(=O)=O.O>[OH:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH:19]([CH3:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([CH3:18])([CH3:17])[CH2:9]1
Reactant: CCc1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Yield: 53 %

Procedure:
A solution of 70% aqueous tert-butyl hydroperoxide (74.8 grams, 609 mmol) is added over 30 minutes to a mixture of 35.0 grams (203 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 2.0 grams of molybdenum trioxide, and 200 ml of ethylbenzene which is preheated to 120° C. The reaction mixture is maintained at reflux temperature throughout the addition, and water is collected in a Dean-Stark trap. The red mixture is heated at reflux for three hours after the addition is complete in order to discharge the red color of the N-oxyl compound. Solids are removed by filtration, and the filtrate is concentrated at reduced pressure to obtain a yellow oil. Purification by flash chromatography (silica gel; 4:1 hexane:ethyl acetate) affords 30.0 grams (53% yield) of the title compound as a white solid melting at 95°-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:40][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:8]2[C:14]([CH3:40])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(c(C)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 130 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (from Example 38(a))(180 mg, 0.29 mmol) in DMF (2.5 mL) was added tetramethyltin (207 mg, 1.16 mmol) and Pd(PPh3)2Cl2 (30 mg, 0.044 mmol). Resulting mixture was stirred at 130° C. for 2 h. Reaction mixture was diluted with EtOAc and filtered. Filtrate was washed with water and brine, dried over MgSO4, filtered, and concentrated to give the title product 161 mg. MS-(+)-ion: M+1=549.14.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-]#[N:13].[Na+].O>C(O)C>[C:6]1([CH2:5][CH2:4][CH2:3][C:2]#[N:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: BrCCCCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCCCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1-bromo-4-phenylbutane (58.8 g, 0.24 mole) and sodium cyanide (25 g, 0.5 mole) in ethanol (300 ml)-water (100 ml) is heated at reflux with stirring for 5 hours. The resulting reaction mixture is concentrated in vacuo and extracted with ether. The ethereal extract is filtered and evaporated at reduced pressure to afford the title compound which is purified by distillation.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][C:21]=4[CH:15]3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][C:21]=4[C:15]3([CH3:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3C2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3(C)C2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-{[4-(ethyloxy)phenyl]sulfonyl}-2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (31 mg) in dry THF (0.5 mL) under argon at −78° C. was added LiHMDS (0.104 mL, 1M, in THF) dropwise. The reaction was stirred at −78° C. for 30 minutes and then the temperature of the cool bath raised to −50° C. over 15 minutes. A solution of methyl iodide (75 μL) in dry THF (1 mL) was made and then 100 μL of this solution added to the reaction dropwise. The reaction was then allowed to warm to −10° C. naturally in the cool bath and then the cool bath removed and the reaction stirred for 20 minutes. LCMS showed good conversion to product. The reaction mixture was concentrated in vacuo and then the mixture taken up in 1:1 MeOH:DMSO and this mixture filtered before purification by MDAP to give the title compound (14 mg) as white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[S:21](Cl)([Cl:24])(=[O:23])=[O:22].O1CCC(OC2C=CC(S(Cl)(=O)=O)=CC=2)CC1>>[O:11]1[CH2:12][CH2:13][CH:8]([O:7][CH2:6][C:5]2[CH:14]=[CH:15][C:2]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccc(COC2CCOCC2)cc1
Agent: O=S(=O)(Cl)c1ccc(OC2CCOCC2)cc1
Agent: [Li]CCCC
Product: O=S(=O)(Cl)c1ccc(COC2CCOCC2)cc1

Procedure:
This compound was prepared from 0.68 g of 4-(4-bromo-benzyloxy)-tetrahydropyran, 2 mL of n-butyllithium (1.6 N in hexane) and 0.81 mL of sulfuryl chloride using the procedure described for 58b. Yield: 0.70 g (oil), 1H-NMR (D6-DMSO): δ=1.41 (m, 2H), 1.86 (m, 2H), 3.32 (m, 2H), 3.54 (m, 1H), 3.79 (m, 2H), 4.53 (s, 2H), 7.30 (d, 2H), 7.61 (d, 2H).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[Cl:10].[C:11]1([Si:17]([C:30]#[CH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I>[C:24]1([Si:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:30]#[C:31][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=2[Cl:10])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C#C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1cc(Cl)c(C#C[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reaction time: 20 h

Procedure:
In an argon atmosphere, 9 g (34.6 mmol) of 1-bromo-2,4,6-trichlorobenzene, 9.8 g (34.45 mmol) of triphenylsilylacetylene, and 15 mL of triethylamine are dissolved in 100 mL of absolute dioxane and at 90° C. combined with 0.2 g (1.04 mmol) of copper (I) iodide and 1.2 g (1.04 mmol) of tetrakistriphenylphosphine palladium and stirred for 20 hours. The reaction mixture is filtered through CELITE® filter aid and the filtrate is evaporated down. The residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/toluene (5:1)). The product is recrystallized from petroleum ether and dried in the vacuum drying chamber at 70° C. Yield: 6.9 g (43% of theory); melting point: 115° C.-120° C.; C26H17Cl3Si (M=463.87); calc.: molecular ion peak (M+H)+: 463/465/467/469; found: molecular ion peak (M+H)+: 463/465/467/469; Rf value: 0.6 (silica gel, petroleum ether/toluene (4:1)).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55].N>ClCCl.CO>[C:54]([NH:64][C@H:65]([C:70]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:71])[CH2:66][CH:67]([CH3:68])[CH3:69])([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 61 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-L-leucine. Yield 61%. Rf 0.50 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(O)cccc21
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2c(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cccc21

Procedure:
In analogy to the procedure described for example 1 d], (4-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[C:24]1C(=O)C(C#N)=C(C#N)C(=O)[C:29]=1Cl.O>O1CCOCC1>[CH2:24]([O:19][C:18](=[O:20])[CH2:17][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=2)[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=1)[CH3:29]
Reactant: Cc1ccc(C(=O)c2cc(CC(=O)O)cc3c2OCC3)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C)cc2)c2occc2c1

Procedure:
7-(4-Methylbenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid (1.0 g) was dissolved in dioxane (20 ml). To this was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.2 g) and the solution heated at reflux for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate, dried with magnesium sulfate and evaporated to dryness. The residue was run on a silica gel column eluting with ethyl acetate/hexane to give ethyl(7-(4-methylbenzoyl)-benzofuran-5-yl)acetate. The acetate was hydrolyzed by the same method set out in Example 3 to give (7-(4-methylbenzoyl)benzofuran-5-yl)acetic acid melting points. This method is especially useful when the 2,3-dihydro starting material contains an alkyl group.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][O:41][CH3:40])[CH:7]=[CH:6][CH:5]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc(-n2nc(OC)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
According to Scheme 9 Step 2: A mixture of 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (100 mg, 0.28 mmol), DMF (4 mL), diisopropylethylamine (95 μl, 0.56 mmol) and methoxyacetyl chloride (30 μl, 0.33 mmol) was stirred under nitrogen at room temperature during 1 hour. The mixture was diluted with 50 mL of a saturated solution of sodium carbonate and the aqueous layer was extracted twice with 50 mL of DCM. The organic layers were combined to be dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 15 g SiO2) using AcOEt/cyclohexane 4/6 as eluant to afford a beige solid. The solid was washed with diethylether to afford N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-2-methoxyacetamide 4.141 (84 mg, 70%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[C:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][C:32]([C:9]2[S:10][C:5]3[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)([OH:35])[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.22 g) in anhydrous tetrahydrofuran (20 ml) stirring at −78° C. was added 2.5M n-butyllithium in hexanes (2.3 mL). The reaction mixture was warmed gradually to −40° C. over 1 hour, cooled to −78° C., and 1-BOC-4-Piperidone (950 mg) was added. The reaction mixture was gradually warmed to room temperature and then left to stir for 2 hours, poured into ice/water and extracted into ethyl acetate. After the usual drying and evaporation of the solvent, the residue was purified by flash chromatography to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-])=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].Cl.C(=O)([O-])[O-:22].[Na+].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH2:17][OH:22])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6]
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CN(C)C=NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 140 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A suspension of N,N-dimethyl-N'-[6-methyl-5-oxido-furo[3,2-c]pyridine-2-sulfonyl]formamidine (4.24 g, 15 mmol) (from Example 13, Step B) in acetic anhydride (13 mL), under a nitrogen atmosphere was heated at 140° C. for 20 minutes to give an amber solution. This reaction mixture was cooled to 100° C. and 6% hydrochloric acid (30 mL) was added. After stirring at 100° C. for 4 hours, the reaction mixture was poured into saturated sodium carbonate (~100 mL) carefully. The product was extracted into methylene chloride, dried over anhydrous sodium sulfate, filtered through a charcoal pad and evaporated to dryness. This residue was triturated with diethyl ether/methylene chloride to give the product (2.21 g, 52% yield) which was used as is.