Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:40][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(F)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To a solution of 78.4 ul (0.555 mmol) diisopropylamine in 2 ml THF were added 347 ul (0.555 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 100 mg (0.427 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one in 1 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. A solution of 180 mg (0.555 mmol) N-fluorobenzenesulphonimide in 1 ml THF was added dropwise. The mixture was stirred at −70° C. for 1.5 hour, quenched with 2 ml of a 20% NH4Cl solution and allowed to warm to room temperature. Water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 58 mg (54%) of the title compound as a light yellow solid. MS (m/e): 253.2 (M+H).
Reaction SMILES: S1C2C=CC(B(O)O)=CC=2N=C1.C([O:15][C:16](=[O:38])[CH:17]([C:23]1[C:24]([I:37])=[C:25]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=3[S:30][C:26]2=[N:27][C:28]=1[CH3:29])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:19]([O:18][CH:17]([C:23]1[C:24]([I:37])=[C:25]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=3[S:30][C:26]2=[N:27][C:28]=1[CH3:29])[C:16]([OH:38])=[O:15])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2sc3c(c2c(I)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
5-Benzothiazole-boronic acid (150 μmol) and ethyl-2-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 11, 1 mL of a 0.1M solution in dioxane, 100 μmol) were added to a reaction vial. A 1M solution of caesium carbonate (2004, 200 μmol) in water was then added, followed by 5 μmol of Pd(dppf)Cl2 and the whole stirred at 100° C. for 16 h before cooling to room temperature and evaporation of the solution under reduced pressure to give a yellow residue. A 2M solution of lithium hydroxide in water (2004, 400 μmol) was added to each vial, followed by 1 mL of THF, and the mixture was shaken at room temperature for 16 h. The pH of the solution was adjusted to neutral using a 1M aqueous solution of hydrochloric acid, before the mixture was evaporated to dryness under reduced pressure and the residue then purified by preparative HPLC on a C18 column, using a mixture of acetonitrile and water as the mobile phase. Evaporation of the appropriate fractions under reduced pressure provided the title compound (11 mg, 23%) as a white solid. ESI/APC(+): 467 (M+H).
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45](C(O)=O)[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CCN(CC)CC>[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH2:46][O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared as an oily product from 12 g of Boc-D-Pro-Arg(NO2)-OBzl, 60 ml of 4 N HCl-AcOEt, 3.3 ml of Et3N, 7 g of Boc-Ser(Bzl)-OH, 4.2 g of HOBt and 5.1 g of DCC in the same manner as in Example 7-(2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([C:10]2[CH:15]=CC=C[CH:11]=2)[OH:9])[CH:7]=1.C([Mg]Br)(C)=C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:8]([OH:9])[C:10]([CH3:15])=[CH2:11])[CH:7]=1
Reactant: OC(c1ccccc1)c1cc(Br)ccc1F
Agent: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cc(Br)ccc1F

Procedure:
Prepared in a similar manner to (5-bromo-2-fluorophenyl)(phenyl)methanol, but using 0.5M isopropenylmagnesium bromide in THF instead of 1M phenylmagnesium bromide in THF. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=6.4, 2.6 Hz, 1H), 7.36 (ddd, J=8.7, 4.5, 2.6 Hz, 1H), 6.96-6.88 (m, 1H), 5.42 (s, 1H), 5.17 (s, 1H), 4.99 (s, 1H), 2.10 (br s, 1H), 1.66 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A stirred solution of 15.3 grams (0.077 mole) of (4-(2-pyridyloxy)phenyl)formaldehyde (a known compound) in 150 mL of methanol was cooled to 0-5° C., and 3.2 grams (0.085 mole) of sodium borohydride was added portion wise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, the reaction mixture was cooled to 5° C. and 150 mL of water was carefully added to destroy excess sodium borohydride. The mixture was cooled to 0° C. and neutralized with concentrated hydrochloric acid. Excess acid was added causing the mixture to be acidic. The mixture was brought to neutrality by the addition of solid sodium bicarbonate. The mixture was concentrated under reduced pressure to remove some of the methanol. The concentrate was taken up in ethyl acetate and washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 12.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[O:2][CH3:1])=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(OC)c(N)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ccc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
2,5-Dimethoxyaniline (0.172 g, 1.125 mmol), triethylamine (0.114 g, 1.125 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.190 g, 1.125 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.149 g, 0.292 mmol, 39%).
Reaction SMILES: B#B.[CH2:3]([N:5]([CH:14]([CH3:27])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:4].Cl>C1COCC1>[CH2:3]([N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]([CH3:27])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[CH3:4]
Reactant: CCCCCCC(=O)N(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCN(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Yield: 100.4 %

Procedure:
A 500 ml 3-neck round bottom flask was fitted with a condenser and glass wool drying tube. The flask was charged with 60 ml of 1M diborane in THF and 7.7 g (0.022 mol) of N-ethyl-N-[1-methyl-4-(4-nitrophenyl)butyl]heptanamide in 50 ml of THF was added dropwise. The resulting reaction mixture was refluxed overnight and cooled. A solution of 25 ml of 2N hydrochloric acid was added dropwise in order to decompose any excess diborane. The mixture was evaporated under reduced pressure and an additional 150 ml of 2N hydrochloric acid was added. This mixture was refluxed for 1 hour, cooled and made basic with 5N sodium hydroxide. The mixture was extracted three times with diethyl ether and the organic phase was washed with water and a saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated to dryness to provide 7.389 g of N-ethyl-N-heptyl-α-methyl-4-nitrobenzenebutanamine as an oil.
Reaction SMILES: [Mg].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6](Cl)[CH2:5][CH2:4]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH:20]([OH:21])[C:19]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=2[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(Sc2ccccc2F)c(C=O)c1
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2ccccc2F)c(C(O)C2CCN(C)CC2)c1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of the Grignard reagent is prepared by reaction of 2.5 g of magnesium with 13.35 g of 1-methyl-4-chloropiperidine (reference above) in 80 ml of tetrahydrofuran in the usual manner. Over 15 minutes with stirring, a solution of 18.2 g of 2-(2-fluorophenylthio)-5-methoxybenzaldehyde in 40 ml tetrahydrofuran is added dropwise and the mixture refluxed for 4 hours. After cooling, it is decomposed with 20% ammonium chloride solution and extracted with benzene. The extract is dried with potassium carbonate and evaporated. There are obtained 23.7 g (100%) crude oily α-(1-methyl-4-piperidyl)-2-(2-fluorophenylthio)-5-methoxybenzyl alcohol which is used for further work without purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH2:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (1.00 g, 5.38 mmol) in CH2Cl2 (20 mL) was added methylamine (4.04 mL, 2M/THF, 8.08 mmol) then to the stirred solution was added sodium triacetoxyborohydride (1.37 g, 6.46 mmol). After stirring at rt for 18 h, the mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The layers were separated then the aqueous extracted with CH2Cl2 (2×30 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography (5% MeOH/CH2Cl2) afforded the desired compound: δH (CDCl3): 2.49 (3H, s), 3.86 (2H, s), 7.31 (1H, d), 7.38 (1H, d), 7.53 (1H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.CN(C=O)C.O.C(OCC)C>[N:33]([CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[N+:34]=[N-:35]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
A solution of (S)-tert-butyl 1-(2,4-dichlorophenyl)-3-hydroxypropan-2-ylcarbamate (50 mg, 0.156 mmol) in DCM (1 mL) was cooled to 0° C. Triethylamine (24 μL, 0.172 mmol) was added, followed by methanesulfonyl chloride (24 μL, 0.312 mmol). The reaction mixture was allowed to warm up slowly to room temperature and was stirred for 4 hours. TLC analysis of the reaction mixture showed no more starting material. Diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the resulting residue was diluted with DMF (0.5 mL), and sodium azide (51 mg, 0.781 mmol) was added. The reaction mixture was heated to 100° C. for 16 hours. LC-MS of mixture showed no more starting material. Water was added (5 mL), and the reaction mixture was extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel (0%-70% EtOAc/hexanes gradient elution to yield (S)-tert-butyl 1-azido-3-(2,4-dichlorophenyl)propan-2-ylcarbamate as an oil (32 mg, 59%). m/z 345 (M+); 1H NMR (CDCl3) δ (ppm) 7.39 (s, 1H), 7.21-7.17 (m, 2H), 4.71-4.68 (m, 1H), 4.07-4.02 (m, 1H), 3.52-3.38 (m, 2H), 2.95-2.86 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH3:20])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.C(Cl)(Cl)Cl>[CH2:18]([C:15]1[N:14]=[C:13]([CH:12]=[CH:11][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:17][N:16]=1)[CH2:19][CH3:20]
Reactant: CCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
5-[2-(3,4-Dimethoxy-phenyl)-vinyl]-3-propyl-[1,2,4]oxadiazole (compound of Example 3, Method A, Step 1; 1.28 g, 4.66 mmol) was dissolved in dichloromethane (15 mL) and cooled to −78° C. A solution of boron tribromide (4.42 mL, 4.66 mmol) in dichloromethane (5 mL), which was cooled to 0° C., was added slowly over a period of 25 min. After 2 h, the reaction mixture was allowed to warm to room temperature (25° C.) and stirred for 2 h. At the end of the reaction, the mixture was quenched by dropwise addition of methanol (15 mL) at 0° C. and stirred for 20 min at room temperature. The solvent was evaporated and the residue obtained was redissolved in 10% methanol in chloroform at 0° C. and stirred with solid sodium carbonate to obtain pH ˜8. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:8][CH2:7]1)=O)C.Cl>>[CH2:12]([N:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Agent: Cl
Product: CCCCCCCCCCN1CCNCC1
Reaction time: 48 h

Procedure:
53.4 Grams of 1-ethoxycarbonyl-4-decylpiperazine is combined with 300 ml. of concentrated hydrochloric acid and refluxed with stirring under a nitrogen atmosphere for approximately 48 hours. After cooling to room terperature the solvents are removed under reduced pressure. The resulting solid is suspended in ethanol, filtered, and air-dried to yield 1-decylpiperazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80° C. for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2×10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH2:4][Si:5](Cl)([Cl:11])[CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].[CH3:14][OH:15]>>[CH3:1][Si:2]([CH3:13])([CH2:4][Si:5]([Cl:11])([O:15][CH3:14])[CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3]
Reactant: CO
Reactant: C[Si](C)(C)C[Si](Cl)(Cl)C[Si](C)(C)C
Product: CO[Si](Cl)(C[Si](C)(C)C)C[Si](C)(C)C
Temperature: 70 °C
Yield: 74 %

Procedure:
13.7 g(50 mmoles) of 2,2,6,6-tetramethyl-4,4-dichloro-2,4,6-trisilaheptane were placed in the flask of the same set as Example 1, and then 1.8 g(60 mmoles) of dry methanol were added. The mixture was heated at 70° C. for 2 hrs. The amount of the product was 9.92 g and the yield 74%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of the title compound of Example 1 (44.3 g, 220 mmol) and Et3N (61.4 mL, 440 mmol, 2 eq) in THF (250 mL) was added dropwise at rt (maintained by cooling from an ice bath), methanesulfonyl chloride (27.77 g, 242 mmol, 1.1 eq). The reaction mixture was stirred for 1 h at rt when TLC (solvent system C) indicated completion. The precipitated Et3NHCl was removed by filtration and the filter cake was washed with 50 mL of THF. The combined flitrate and washings were evaporated in vacuo to give the crude product as a yellow oil. This was dissolved in EtOAc/hexanes (1:2) and passed through a pad of silica gel eluting with ethyl acetate/hexanes (1:3). Evaporation of the flitrate afforded the product as a pale yellow oil (59.1 g, 96%) which crystallized on standing. Recrystallization from EtOAc/hexane (1:10) afforded an analytically pure sample of the title compound: mp 69°-70° C.; 1H-NMR (CDCl3) ∂ 4.72 (m,1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.32 (m, 1H), 3.05 (s, 3H), 1.75-2.06 (complex m, 4H), 1.46 (s, 9H); CIMS (MH+ calcd for C11H21NO5S): 280. Found (MH+): 280; Anal. (calcd for C11H21NO5S): C, H, N.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5]Cl.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:16]=[C:17]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:19]>CN(C=O)C>[F:42][C:39]([F:40])([F:41])[C:37]1[CH:36]=[C:17]([CH:16]=[C:15]([C:14]([F:13])([F:43])[F:44])[CH:38]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:5][C:4]#[C:3][CH2:2][Cl:1])[CH2:22][C@H:21]1[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:19]
Reactant: ClCC#CCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
22 ml 1,4-dichloro-2-butine was added to a suspension of 43 g K2CO3 in 100 ml DMF at 20° C. under a protective gas atmosphere. The mixture was heated to 50° C. and then a solution of 50 g (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine in 200 ml DMF was added dropwise to this receiving solution. The resulting mixture was stirred for 5 hours at 50° C. Stirring was continued overnight at room temperature, undissolved precipitate was filtered out, and the precipitate was washed twice with 200 ml portions of ethyl acetate. The combined filtrates were evaporated to dryness in a vacuum, and the resulting oil was purified by column chromatography (silica gel; mobile solvent: n-hexane/ethyl acetate 60/40 to 30/70). The combined product fractions were again evaporated to dryness. 40.4 g of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]2-(1H-indol-3-ylmethyl]-4-(4-chloro-2-butin-1-yl)piperazine was obtained as an amorphous yellowish solid, which was used for the next synthesis stage without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]#[C:11][CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:11]([CH3:12])=[CH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:17][CH:16]=1
Reactant: CC#CS(=O)(=O)c1ccccc1
Reactant: COc1ccc(N)cc1
Solvent: CO
Product: COc1ccc(NC(C)=CS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A stirred solution of 1-phenylsulphonylpropyne (0.25 g) in anhydrous methanol (10 ml) was treated with 4-anisidine (0.17 g) and the homogeneous mixture was allowed to stand at room temperature overnight. The methanol was removed in vacuo to give 1-(4-methoxyphenylamino)-1-methyl-2-(phenylsulphonyl)ethene (0.4 g) in the form of a dark brown oil [NMR (in deuterated dimethylsulphoxide: 2.16, 3.76, 7.04, 7.62, 7.84, 8.68 ppm].
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH3:4].[NH2:7][N:8]1[C:12]([NH2:13])=[N:11][N:10]=[C:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:3]([CH3:4])=[N:13][C:12]2[N:8]([C:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:10][N:11]=2)[N:7]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: CC(=O)C(C)=O
Product: Cc1nc2nnc(Cc3ccc(O)cc3)n2nc1C

Procedure:
General procedure A was followed with the reaction of butane-2,3-dione and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-(6,7-dimethyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (example 8).