Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10].[OH-].[Na+].Cl>O>[Cl:5][CH2:6][CH2:7][CH2:8][S:9]([N:3]([CH3:4])[CH3:2])(=[O:11])=[O:10]
Reactant: CNC
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)CCCCl
Temperature: -5 °C

Procedure:
10 g of dimethylamine hydrochloride are placed in 60 ml of water, a nitrogen atmosphere is applied and the solution is cooled to between 0° C. and −5° C., and then 18 ml of 3-chloro-1-propanesulphonyl chloride are added dropwise. 10.6 g of sodium hydroxide in 40 ml of water are added while maintaining at −5° C., then the mixture is allowed to return to AT and stirring is maintained for 1 hour. 1 ml of concentrated HCl is added and then extraction is carried out with DCM. The organic phase is washed with a 10% NaOH solution and then with an NaCl solution. 15.1 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]>CO>[CH3:1][N:2]([CH3:3])[S:13]([C:10]1[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a stirring solution of dimethylamine (180 mL, 40% in water, 1.57 mol) in methanol (180 mL) at 0° C., was slowly added 4-nitrobenzenesulfonyl chloride (69.5 g, 314 mmol). After complete addition, the cold bath was removed; and, after stirring overnight, the mixture was filtered and the precipitate was washed with water and dried in vacuo to give 68 g (94%) of tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Si](C)(C)[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C1COCC1>[OH:17][CH:16]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:15]1[CH:18]=[CH:19][C:12]([OH:11])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: Cc1ccc(Br)nc1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc(O)cc2)nc1
Temperature: -40 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 2-bromo-5-methylpyridine (3.45 g, 20 mmol) in THF (10 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (12 mL, 19.2 mmol) over a 10-min period at −78° C. The mixture was stirred at −78° C. for 2 min before 4-trimethylsilyloxybenzaldehyde (4.2 g, 21.6 mmol) dissolved in THF (10 mL) was added. The mixture was allowed to warm to −40° C. and quenched with water. The pH of the aqueous phase was adjusted to 7 which causes precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol. This was isolated by filtration to give 1.13 g (27%) of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol as crystals. This intermediate was dissolved in CH2Cl2 (15 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at 50° C. Evaporation gave 99% of 4-(5-methyl-pyridin-2-ylmethyl)phenol as a hygroscopic solid. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent and N-phenyl-N-methyl carbamoyl chlorid) to give 99% of the title product as its crystalline hydrochloride after purification by flash chromatography (Quad flash 12, EtOAc-heptane) and treatment with HCl in Et2O.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 1-(2-nitro-phenyl)-piperazine (4.53 g) (commercially from Emkachem) and 3,4-dichlorobenzyl bromide (4.6 g) in 100 mL of dichloromethane was treated with triethylamine (3.4 mL). The reaction was stirred at ambient temperature under inert atmosphere overnight. After solvent removal, the crude reaction mixture was subjected directly to flash chromatography using silica. Elution with hexanes, then 20% ethyl acetate in hexanes, and finally 33% ethyl acetate in hexanes furnished the product as an oil (6.4 g), which was carried on as is.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1>C(Cl)Cl>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:19][CH2:20][CH:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1)(=[O:16])=[O:15]
Reactant: OCC1COc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
Triethylamine (4.2 ml, 30 mmol was added, in one portion, and then, in portions, para-toluenesulfonyl chloride (5.7 g, 30 mmol was added, to a solution of 2-hydroxymethyl-1,4-benzodioxane (Maybridge, 5 g, 30 mmol) in methylene chloride (50 ml). A mild exothermic reaction ensued. The reaction mixture was stirred overnight. Precipitated triethylamine hydrochloride was separated by filtration and washed with methylene chloride (50 ml). The organic medium was washed with 10% aqueous hydrochloric acid (50 ml , water 50 ml , brine (30 ml), and dried over sodium sulfate. Purification of the crude product by column chromatography (400 g fine silica, hexane-ethyl acetatetriethylamine; 100:100:1) yielded pure (1,4-benzodioxan-2-yl)methyl tosylate (66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH3:22])[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH:10]=C)([CH3:4])([CH3:3])[CH3:2].[O:24]=[O+][O-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH3:22])[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH:10]=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCN(C(=O)OCc1ccccc1)[C@H](C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@H](C(=O)OC(C)(C)C)N(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Cbz-N-allyl-D-alanine t-butylester (70) in methylene chloride is treated with ozone at -78° C. until a blue color persists. The ozonide is quenched with dimethylsulfide and allowed to warm to room temperature. Excess dimethylsulfide is removed by bubbling a stream of nitrogen into the solution. After evaporation of solvent the product is purified by flash chromatography over silica gel to give (71).
Reaction SMILES: C([C:6]1[C:7]([S:17]([NH:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:19])=[O:18])=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)(OCC)=O.Cl.O>CC(O)=O>[CH3:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]2[N:8]=[C:7]([S:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:18])=[O:19])[CH:6]=[C:10]2[N:11]=1
Reactant: CCOC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)nn2c(C)cc(C)nc12
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(F)cccc3F)cc2n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A slurry of 4.8 g (10.8 mmole) of 3-carboethoxy-5,7-dimethyl-N-(2,6-difluorophenyl)pyrazolo-[1,5-a]pyrimidine-2-sulfonamide in 30 ml glacial HOAc was stirred at room temperature with 1 ml concentrated HCl and 3 ml water for 2 hours. The mixture was then heated at 110° C. for 16 hours. A further 1 ml concentrated HCl and 5 ml water were added and the mixture stirred for 16 hours, then cooled to room temperature. The mixture was thrown onto ice and the resultant solid collected by filtration, washed with water and dried to give 2.34 g (64 percent) of the product as a brown powder, m.p. 201°-208° C. An analytical sample was recrystallized from CH3CN/EtOAc/CH3OH, m.p. 209°-211° C. (dec). 1H NMR (DMSO-d-6) 10.3 (s, 1H, NH), 7.37 (m, 1H, benzene), 7.10 (m including s, 3H, aromatic and H-3 or H-6), 6.82 (s, 1H, H-3 or H-6), 2.63 (s, 3H, CH3), 2.53 (s, 3H, CH3) IR (KBr): 3400, 3050, 2800, 1625, 1600, 1540, 1480, 1430, 1325, 1290, 1240, 1170, 1140, 1000.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]4)=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)CC1
Yield: 9.9 %

Procedure:
The title compound (10 mg, 8%) was prepared as a white solid from [4-(4-morpholinylsulfonyl)phenyl]boronic acid (54 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.78 (m, 2H), 7.70 (m, 2H), 7.54 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.97-4.86 (m, 1H), 4.22 (bs, 2H), 3.86 (d, 2H, J=6.4 Hz), 3.78-3.73 (m, 4H), 3.07-3.01 (m, 4H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.91-1.81 (m, 2H), 1.37-1.27 (m, 2H), 1.25 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 503 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15].FC(F)(F)S(O[CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[O:3][CH2:22][CH2:23][O:24][C:25]([F:28])([F:27])[F:26])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Reaction time: 0.17 h

Procedure:
To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under N2 was added methyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0 mmol) and the mixture was stirred for 10 min. 2-(Trifluoromethoxy)ethyl trifluoromethanesulfonate (prepared according to the procedure described by Blazejewski, et. al. JOC, 2001, 66(3), 1061-1063) (1.2 g, 4.6 mmol) was then added dropwise and the solution was stirred at room temperature for 2 h, then at 50° C. for 2 h. The mixture was concentrated to a solid, and the residue was taken up in 50 mL of DCM before it was washed with brine (20 mL), dried over MgSO4 and purified by column chromatography (0-25% EtOAc/hexane) to give methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid. ESI-MS m/z calc. 294.1. found 295.3 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:53][C:51]5[N:52]=[C:48]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[S:49][CH:50]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: -50 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.800 g, 2.52 mmol), triphenylphosphine (0.992 g, 3.78 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.555 g, 2.90 mmol) in a 200 mL flask fitted with an addition funnel was maintained under vacuum for ten minutes. The mixture was then flushed with nitrogen and charged with dry tetrahydrofuran (60 mL, distilled over lithium aluminum hydride). The solution was warmed to −50° C. and then sonicated for 5 min. The cooled heterogeneous mixture was then treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.663 g, 3.28 mmol) in tetrahydrofuran (15 mL), added dropwise over 2.5 h. The reaction was homogeneous (pale yellow) at the end of the addition. The mixture was then stirred for another 2.5 h (total 5 h). The reaction mixture was then diluted with dichloromethane (400 mL), washed with saturated sodium bicarbonate (20 mL), brine and dried (anhydrous magnesium sulfate). Evaporation gave a white solid which was chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3). The fractions were collected and evaporated to give the desired compound (1.40 g) as a white solid, contaminated with hydrazide by tlc. Crystallization in ethyl acetate (40 mL) gave the pure title material (0.838 g, 68%) as a white solid. The mother liquors (0.475 g) were chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3) to give after crystallization from ethyl acetate (30 mL) to provide additional desired compound (0.160 g, 13%, total 81%) as a white solid. LC (Method C): 2.480 min. HRMS (ESI) calcd for C24H19N4O4S2 [M+H]+ m/z 491.0842, found 491.0865. 1H NMR (CDCl3, 400 MHz) 3.85 (s, 3H) 4.21 (s, 3H) 5.33-5.55 (m, 2H) 6.48 (d, J=1.96 Hz, 1H) 6.72 (dd, J=1.96, 0.78 Hz, 1H) 7.12 (s, 1H) 7.36-7.39 (m, 1H) 7.41-7.50 (m, 3H) 7.86 (s, 1H) 7.95-8.02 (m, 2H).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][I:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[I:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: ICCOCCOCCOCCI
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(CCOCCOCCOCCI)OCC
Temperature: 160 °C

Procedure:
1-iodo-2-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)ethane (1 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the product as a yellow oil.
Reaction SMILES: C[O:2][CH:3]=[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])[CH3:5].Cl>C1COCC1.C(OCC)(=O)C>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:10][C:6]=1[CH:4]([CH3:5])[CH:3]=[O:2]
Reactant: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Yield: 52.4 %

Procedure:
5-(2-Methoxy-1-methyl-vinyl)-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (7.0 g, 22.3 mmol) in THF (200 mL) is treated with concentrated HCl aqueous solution (7 mL) at 50° C. for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with sodium bicarbonate aqueous solution, dried over sodium sulfate. Concentration and column chromatography on silica gel provided the title compound (3.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)nc1C(=O)NCC1CC1
Reaction time: 16 h
Yield: 27.6 %

Procedure:
6-Chloro-3-methylpyridine-2-carboxylic acid (595 mg, 3.47 mmol), aminomethylcyclopropane (356 μL, 4.16 mmol), EDC.HCl (1.46 g, 7.63 mmol), HOBN (1.54 g, 8.67 mmol) and NEM (1.10 mL, 8.67 mmol) were dissolved in DCM (30 mL) and stirred for 16 h. The reaction mixture was washed with sat aq NaHCO3 (30 mL), 1M aq HCl (30 mL), brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (215 mg, 28%) as a yellow solid. LCMS (ES+): 225.5 [MH]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2cccc(Br)n2)CCOCC1
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 6-bromo-pyridin-2-ylcarbamate (136 mg, 0.50 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 40 mg, 1.0 mmol) under stirring. The resultant mixture was stirred at room temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate O, 152 mg, 0.506 mmol) in DMF (1.5 ml) was then added. The resulting mixture was then stirred at 85° C. for about 18 hours. The mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried with sodium sulfate. After concentration the residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to give the desired title compound as a viscous oil (92 mg, 46% yield), which solidified upon standing overnight. LCMS (m/z): 403.1[M+H]+; Rt=1.026 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous potassium carbonate (1.38 g, 10 mmol), 10 ml of dimethylsulfoxide, and 20 ml of 1,2-dichloroethane are combined and heated to reflux. HPLC shows the reaction is at equilibrium at about 1 hour. Therefore, another equivalent of potassium carbonate is added. After the second addition of potassium carbonate, the ratio of product to bis alkylated biproduct is greatly enhanced. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The organic layer is back extracted with 20 ml of brine and then filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling. This crude product is redissolved in 12 ml of hot methanol and water is added (total of 6 ml) dropwise until crystals appear. The crystallization is allowed to continue for one hour with cooling. The precipitate is filtered and rinsed with 12 ml of 1:1 methanol:water. The filter cake is dried in vacuo at about room temperature to give 2.00 g of product. (93.5%). HPLC.
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:26]([OH:28])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([N:8]([CH3:29])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:26]([OH:27])[OH:28])[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[C:43]([C:42]2[S:41][C:40]3[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=3[C:38]=2[Cl:37])=[O:44])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boronic acid 11 (700 mg, 1.72 mmol) in DCM (15 mL) at 0° C. is treated with triethylamine (0.48 mL, 3.45 mmol), followed by 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (439 mg, 1.90 mmol) in one portion. After warming to RT, the solution is stirred 16 h. Analysis by LC/MS at this juncture confirmed the reaction is complete. Thus the reaction is diluted with aqueous NaHCO3 (20 mL) and extracted into EtOAc (3×25 mL). The combined EtOAc phases are dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(=O)C)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.Cl.[OH-].[Na+].ClCCl>C(O)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)[CH2:5]1
Reactant: CC(=O)N1CCN(c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N3CCNCC3)cc2)C[C@H](C)O1
Yield: 36.9 %

Procedure:
A mixture 1-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]ethanone (11.37 g) and 1.0 mol/l hydrochloric acid (225 ml) in ethanol (220 ml) was refluxed for 23 hours. The reaction mixture was added to a mixture of 1.0 mol/l sodium hydroxide solution and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give cis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine (3.64 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13]>C(O)C>[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CCl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccc(CCl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
4-Chloromethylbenzaldehyde (11.93 g, 77.17 mmol) was dissolved in ethanol (200 ml), hydroxylamine hydrochloride (10.73 g, 154.41 mmol) was added, and the mixture was stirred at 50° C. for 3 hours. Ethanol was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (12.69 g, 97%).