Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2cccs2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophene carboxaldehyde (12.5 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 8 as a colorless oil (25.2 mg, 82%). LRMS 343.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCC#CC=CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (22.4 g., 0.12 moles) and 50 ml. of anhydrous pyridine is added 14 g. of non-4-en-6-yn-1-ol (0.107 moles) with ice bath cooling. The mixture is stirred for 1 hour and then is stored at 0° overnight. Ice is added to the mixture which is extracted with several portions of 50:50 ether/hexane. The combined organic phase is washed with 5% HCl, water, saturated sodium bicarbonate and dried over sodium sulfate. Removal of solvent at reduced pressure and subsequent solvent removal at 0.1 mm. for 1 hour gives 1-tosyloxy-non-4-en-6yne (28 g.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27]C(C)(C)[O:29]3)[C@H:25]([N:33]3[C:37]4[N:38]=[CH:39][N:40]=[C:41]([NH:42]CC5C=CC(OC)=CC=5OC)[C:36]=4[CH:35]=[CH:34]3)[O:24]2)[CH:19]([CH3:21])[CH3:20])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[O:24][C@H:23]([CH2:22][N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=4)=[O:13])[C@@H:30]([OH:29])[C@H:26]3[OH:27])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
1-(4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)propyl)urea (1.07 g, 1.39 mmol) was dissolved in a mixture of trifluoroacetic acid (25 mL) and water (2.5 mL) which had been cooled at 0° C. and the resulting solution was stirred at 0° C. for 30 minutes, then warmed to room temperature. After 4 h, the reaction was found to be complete by HPLC. The reaction mixture was concentrated in vacuo and the residue was taken up in 25 mL MeOH (white slurry) and concentrated. This process was repeated three times and the resultant residue was placed under high vacuum. The material was taken up in 100 mL 10% MeOH/CH2Cl2 and washed with two 75 mL portions of sat NaHCO3 and 50 mL 1% aq Na2CO3. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/solid. The crude material was purified by flash chromatography (100 g silica gel, 5-10% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (0.35 g, 46%) as a colorless glass: MS (ESI+) for C28H41N7O4 m/z 540.3 (M+H)+; (ESI−) for C28H41N7O4 m/z 538.3 (M−H)−, m/z 584.4 (M+HCO2)−; HPLC purity 98% (ret. time 2.86 min); 1H NMR (400 MHz, d4-MeOH) ppm 8.05 (s, 1H), 7.27 (d, J=3.73 Hz, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 6.63 (d, J=3.73 Hz, 1H), 6.15 (d, J=4.77 Hz, 1H), 4.46 (t, J=5.08 Hz, 1H), 4.18 (t, J=5.39 Hz, 1H), 4.11 (m, 1H), 3.22 (m, 2H), 3.07 (m, 1H), 2.85 (m, 1H), 2.72 (m, 1H), 2.60 (t, J=6.43 Hz, 2H), 1.68 (m, 2H), 1.28 (s, 9H), 1.05 (d, J=6.63 Hz, 3H), 1.01 (d, J=6.43 Hz, 3H).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16]O)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:40][C:41]([NH:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:42])[CH:38]=[CH2:39].C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:43]([S:44](=[O:45])(=[O:46])[NH2:47])[C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)NS(N)(=O)=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (8.02 g: ca. 30 mmole) in ethyl acetate (83 ml) under ice cooling, triphenylphosphine (9.44 g: 13.6 mmole), N-allyloxycarbonylsulfamide (3.12 g: 15.9 mmole), and azodicarboxylic acid diethylester (5.67 ml: 36 mmole) are successively added. The mixture is stirred under ice cooling for 55 minutes and at room temperature for 4 hours. The reaction mixture is dissolved in toluene (60 ml), concentrated, diluted with toluene (60 ml), filtered to remove separating crystals, and the filtrate is concentrated. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.74 g). Yield: 55%. Colorless oil. NMR δ(CDCl3) ppm: 1.5 to 1.7(m, 1H), 2.35(s, 3H), 2.5 to 2.7(m, 1H), 3.19 (dd, J=6.3 Hz, J=11.5 Hz, 1H), 3.68 (dd, J=3.8 Hz, J=14.5 Hz, 1H), 3.9 to 4.3(m, 3H), 4.3 to 4.7(m, 5H), 5.2 to 5.4(m, 4H), 5.8 to 6.1(m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:36][N:37]=[C:38]=[O:39]>C(Cl)Cl>[CH3:36][NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:39]
Reactant: CN=C=O
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCc2cc(OC)c(OC)cc2C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A stirred solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (487.6 mg, 1.306 mmoles) in methylene chloride (5 mL) at 0° C. was treated with triethylamine (0.24 mL, 1.3 equiv.) and methyl isocyanate (0.10 mL, 1.3 equiv.). The mixture was immediately allowed to warm to room temperature. After 4 hours, the mixture was evaporated and the residue partitioned between ether and 2% phosphoric acid. The organic phase was washed with 1M sodium hydroxide and brine, dried over sodium sulfate, and evaporated to give a solid foam that was triturated with hexane to give the product as a white solid (494.8 mg, 88%). 1H-NMR (CDCl3) δ 2.45 (m, 1H), 2.65-3.10 (m, 3H), 2.73 (s, 3H), 3.38 (m, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 3.90 (m, 2H), 4.03 (t, 1H), 4.45 (m, 1H), 6.38 (s, 1H), 6.58 (s, 1H), 7.32 (m, 10H). Mass spec. 431.2 (MH)+. Anal. Calc. for C27H30N2O3: C-75.32, H-7.02, N-6.51. Found: C-75.04, H-7.13, N-6.35.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
A suspension of 5-bromo-1H-indazole (200 mg, 1.02 mmol), cesium carbonate (661 mg, 2.00 mmol), and iodomethane (156 mg, 1.10 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 h. The mixture was partitioned between 5% lithium chloride and ethyl acetate, the aqueous layer was extracted with ethyl acetate (2×), the combined organic extracts were washed with 1 N sodium hydroxide, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) gave 5-bromo-1-methyl-1H-indazole (150 mg, 70% yield) as an orange solid. MS (EI) for C8H7BrN2: 212 (MH+).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:36]2[CH2:38][O:37]2)=[CH:30][C:29]=1[F:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[F:47][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:28]=1[O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C@H:36]([OH:37])[CH2:38][NH:17][C:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H]1CO1
Reactant: CC(C)c1cccc(C2(N)CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C2(NC[C@@H](O)[C@H](Cc3ccc(OCc4ccccc4)c(F)c3)NC(=O)OC(C)(C)C)CCCCC2)c1
Reaction time: 72 h
Yield: 53.4 %

Procedure:
The free base (270 mg, 1.24 mmol) of 1-(3-isopropylphenyl)cyclohexanamine hydrochloride 3 is obtained as a colorless oil by neutralization of the salt with 1N NaOH, extraction into ethyl acetate, drying over Na2SO4, and concentration. This is dissolved in 10 mL of CH2Cl2, and to it is added compound 17 (280 mg, 0.73 mmol) and 1.25 g of silica gel. The solvent is removed in vacuo and the reactants on silica are allowed to stand at ambient temperature for three days. The product mixture is eluted from the silica with 10% methanol in CH2Cl2, concentrated, and chromatographed on silica gel, eluting with 4% methanol (containing 2% NH4OH) in CH2Cl2, to afford compound 18 (238 mg, 0.39 mmol, 54%) as a colorless oil: 1H NMR (CDCl3) δ 7.43–7.26 (m, 8H), 7.12 (m, 1H), 6.94–6.84 (m, 3H), 5.09 (s, 2H), 4.64 (d, J=9 Hz, 1H), 3.80 (br, 1H), 3.31 (br, 1H), 2.92–2.83 (m, 2H), 2.7 (m, 1H), 2.37 (m, 2H), 2.0–1.95 (m, 4H), 1.67–1.50 (m, 5H), 1.35 (s+m, 10H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:42][N:43]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CN(c1ccccc1)c1ccc(F)cc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 1 h then was concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methyl-N-(4-fluorophenyl)aniline (0.50 mL, 3.5 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS) then quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 570.1(M+Na); 526.0 (M+H-MeOH).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[S:3][CH2:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:4]3[S:3][CH2:2][S:1][CH:5]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)C1=CSCS1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CSCS1
Yield: 38.7 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 1,3-dithiole-4-carboxylic acid (4.6 g), N,N'-carbonyldiimidazole (7.5 g) and 2-amino-7-chloro-1,8-naphthyridine (4.2 g). The product obtained by precipitation in water (4.8 g) is taken up with boiling acetonitrile (300 cc), the insoluble material is removed by filtration, and the filtrate is poured into water (500 cc). The precipitate obtained is purified by recrystallization in an acetonitrile/water (5:2 by volume) mixture (650 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)- 1,3-dithiole-4-carboxamide (2.8 g), m.p. 235° C., is thereby obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>O1CCCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: CCCBr
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)cc3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of tetrahydrofuran (hereafter abbreviated as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.1 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-4-fluorobiphenyl to obtain 4'-(trans-4-n-propyl-4-silacyclohexyl)-4-fluorobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:57]4[CH2:56][CH2:55][N:54]([CH2:53][CH:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH2:59][CH2:58]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCN(CC2CCN(C)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.40 g (1.10 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 0.18 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine were dissolved in 10 ml of MeCN. The solution was then cooled down to 0° C. and 0.32 g=0.35 ml (3.2 mmol) of N-methylmorpholine was added drop by drop. After 2 hours stirring at 0° C., a solution of 0.21 g (1.1 mmol) 1-(1-methyl-piperidin-4-ylmethyl)-piperazine in 3 ml of MeCN was added drop by drop. Then, the mixture was warmed up to RT and stirring continued for 20 hours. Subsequently, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0-7.5:2.5) to afford the title compound as colorless solid. MS: 560.2 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][OH:51])=[CH:43][CH:42]=2)[CH:34]=1)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][O:51][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][CH:46]=2)[CH:34]=1)(=[O:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCOS(C)(=O)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Methanesulfonyl chloride (41 μL, 0.53 mmol) and triethylamine (80 μL, 0.58 mmol) were added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-hydroxybutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (22, 247 mg, 0.44 mmol) in 5 mL CH2Cl2 and stirred at room temperature for 2 hours. The reaction was quenched with 1N aqueous HCl. The aqueous layer was extracted two times with EtOAc. The combined organic layers were washed with H2O and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide the product 23 (279 mg, 99% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (s, 2 H), 7.02-7.11 (m, 3 H), 7.00 (d, J=7.8 Hz, 2 H), 5.33 (dd, J=9.6 Hz, 1 H), 5.21 (dd, J=9.6 Hz, 1 H), 5.12 (dd, J=9.6 Hz, 1 H), 4.48-4.56 (m, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 4.24 (t, J=6.1 Hz, 1 H), 3.93 (d, J=3.8 Hz, 2 H), 2.99 (s, 3 H), 2.62 (t, J=7.2 Hz, 2H), 2.22 (s, 3 H), 2.15-2.20 (m, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.70-1.81 (m, 4 H). MS (ES+) [M+NH4]+=654.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:15]/[CH:13]=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCC#Cc1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C/C=C/CCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
5-Phenylpent-4-ynal (0.5 g) in CH2Cl2 (5 ml) was added to a solution of formylmethylenetriphenyl phosphorane (1.8 g) in CH2Cl2 (10 ml) and the mixture was stirred at room temperature under a dry nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was slurried with ether (50 m), filtered, and the residue washed with ether. The ethereal solutions were combined and the product was purified by chromatography on silica eluting with ether:hexane (1:9) to yield 7-phenylhept-2E-en-6-ynal (0.25 g) as a yellow oil.
Reaction SMILES: NCCSCCC1N=CNC=1.[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([O-:23])=[O:22].[NH2:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=1>>[N+:21]([CH:24]=[C:25]([NH:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=1)[NH:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([O-:23])=[O:22]
Reactant: CSC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1
Reactant: NCCSCc1ncccc1Cl
Agent: CSC(=C[N+](=O)[O-])SC
Agent: NCCSCCc1c[nH]cn1
Product: O=[N+]([O-])C=C(NCCSCCc1c[nH]cn1)NCCSCc1ncccc1Cl

Procedure:
4-[2-(2-Aminoethylthio)ethyl]imidazole (from the dihydrobromide (4.0 g) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-(2-(4-imidazolyl)-ethylthio)ethylamino]ethylene is treated with 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine by the procedure of Example 1 (a) (ii) to yield the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A mixture of 6-bromopicolinic acid (2.02 g, 10 mmol), phenyboronic acid (1.22 g, 10 mmol), cesium carbonate (5.00 g) and PdCl2 [(t-Bu)2P(OH)]2 (70 mg, CombiPhos Catalysts, Inc. Princeton, N.J.) in DMF (20 mL) and water (3 mL) was purged with Ar-gas and heated at 110° C. for 24 h. The reaction was incomplete and did not progress further. To the reaction mixture were added EtOAc (200 mL) and 1 N aq. HCl (40 mL). The EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (350 mg, 18%) as a white solid. 1H NMR (CDCl3) δ 10.45 (s, 1H), 8.18–7.96 (m, 5H), 7.51–7.53 (m, 3H).