Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:28]2[O:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:29][CH3:30])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:28]2[O:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:29][CH3:30])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)OCCO1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (53 mg, 0.33 mmol) with compound 518 (74 mg, 0.25 mmol) in THF (1.5 mL) in the presence of LiHMDS (0.75 mL, 0.75 mmol) afforded compound 126 as a white solid material after purification by column chromatography (60-80% EtOAc in light petroleum). LC-MS: RT=3.63 min.; m/z 426.18, 428.16 (M+H)+. 1H NMR (DMSO-d6): δ 8.64 (2H, s), 7.39 (1H, d, J 8.8), 6.86 (1H, d, J 8.9), 4.60 (2H, s), 4.34 (2H, s), 4.17 (2H, s), 3.97 (4H, s), 3.84 (3H, s).
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].Cl[CH2:18][C:19](=[O:31])[CH2:20][C:21]1[C:22]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=2[S:24][CH:25]=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:18][C:19](=[O:31])[CH2:20][C:21]1[C:22]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=2[S:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1csc2ccc(Cl)cc12
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1csc2ccc(Cl)cc12
Yield: 57 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(5-chlorobenzo[b]thiophen-3-yl)-propan-2-one (4.43 g, 17.1 mmol) with acetic acid (2.0 mL, 2.1 g, 35 mmol) and triethylamine (4.9 mL, 3.6 g, 35 mmol). Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product, a pale yellow solid (2.76 g, 57% yield): 1H NMR (400 MHz, CDCl3) δ2.16 (s, 3H) 3.94 (d, J=1.0 Hz, 2H) 4.73 (s, 2H) 7.34 (ddd, J=8.6, 2.0, 0.5 Hz, 1H) 7.39-7.42 (m, 1H) 7.65 (d, J=2.0 Hz, 1H) 7.78 (dd, J=8.6, 0.5 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].CO>O1CCOCC1>[ClH:24].[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:17]1[NH:16][N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3nccs3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1csc(-c2nc(C3CCNCC3)n[nH]2)n1

Procedure:
The mixture of 7.59 g of the crude product obtained in step 4 is dissolved in dioxane and 68 ml hydrogen chloride 4M sol. in dioxane is added slowly. The product appears as an oil. After addition of 542 ml methanol the oil is dissolved. The solution is stirred over night until precipitation of the crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)=[N:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[N:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)=[N:23][CH:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc(-c5cccc(Cl)c5)nc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1cnc(-c2cccc(Cl)c2)nc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(3-chlorophenyl)pyrimidin-5-ylcarbamoyl)phenoxy)chroman-4-carboxylate (45 mg, 0.080 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (399 μl, 0.40 mmol) and ethanol (500 uL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a 0.5 mm preparative TLC plate eluting with 10% methanol/DCM to yield the desired compound (15 mg, 0.028 mmol, 35% yield) MS (ESI)=536.1 (M+H).
Reaction SMILES: C1[O:18][CH2:17][CH2:16]OCCOCCOCCOCCOC1.FC(F)(F)COP(CC(OC)=O)(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:48][S:49][C:50]1[N:55]=[C:54]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53]([CH:62]=O)=[C:52]([NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:51]=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)C>[CH3:48][S:49][C:50]1[N:55]=[C:54]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53]2[CH:62]=[CH:16][C:17](=[O:18])[N:64]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:52]=2[N:51]=1
Reactant: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (81 μL, 0.38 mmol, 1.2 eq) in anhydrous THF (20 mL) was cooled to −78°. To this solution was added potassium bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene. This solution was stirred for additional 30 min at −78° and 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde (102 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was then stirred for 8 h at −78° and warmed to 23° and stirred 16 h. Sat'd aq. NH4Cl (5 mL), followed by diethyl ether (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by flash chromatography to afford 100 mg (91% yield) of pure 2-methylsulfanyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.19 (s, 3H), 6.70 (d, 1H, J=9.9 Hz), 7.26 (m, 2H), 7.42-7.83 (m, 8H), 7.88 (d, 1H, J=9.9 Hz), LC MS (m/e)=346 (MH+).
Reaction SMILES: C1([Si](OC)(OC)[O:8]C)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.CO[Si](CCC[CH:48]1[CH2:53][C:52](=[O:54])[O:51][C:49]1=[O:50])(OC)OC.C(OCCC[Si](OC)(OC)OC)C1OC1.Cl.C(OCC(O)C)C.[OH-].[C:79]1([S+:85]([C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>O.C(O)C.CC(C)=O>[C:52]([O-:51])(=[O:54])[CH2:53][CH2:48][C:49]([O-:50])=[O:8].[C:92]1([S+:85]([C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1.[C:92]1([S+:85]([C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1
Reactant: CO[Si](CCCC1CC(=O)OC1=O)(OC)OC
Reactant: CO[Si](OC)(OC)c1ccccc1
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.81 g of phenyltrimethoxysilane, 70.74 g of tetraethoxysilane, 17.21 methyltriethoxysilane, 0.14 g of trimethoxysilylpropyl succinic anhydride, 5.73 g of glycidoxypropyltrimethoxysilane, and 150 g of acetone were charged into a 500 ml flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 32.33 g of a 0.01 M hydrochloric acid aqueous solution was added to the mixed solution. The reaction was carried out for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol, water, and hydrochloric acid being reaction by-products were distilled off under reduced pressure to obtain a hydrolysis-condensation product. To the hydrolysis-condensation product, 1.36 of a 10% by weight triphenylsulfonium hydroxide aqueous solution was added to obtain a triphenylsulfonium succinic acid salt-containing Si polymer. The obtained polymer corresponded to a polymer having five types of unit structures of Formula (3-34). The molecular weight Mw of the obtained polymer measured by GPC was found to be 2,500 in terms of polystyrene.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.[F:17][C:18]([F:37])([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)O>ClCCl>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([F:7])[C:18]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])([F:37])[F:17])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(O)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(C(F)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Yield: 71.6 %

Procedure:
A solution of 0.24 mL (1.8 mmol) of diethylaminosulfur trifluoride in 5 mL of dichloromethane was cooled to -78° C. (dry ice-acetone bath) and treated dropwise with a solution of 0.50 g (1.6 mmol) of 2,2-difluoro-1-(4-methylphenyl)-2-phenylsulfonylethanol in 2 mL of dichloromethane. The cooling bath was removed and 30 minutes later 2 mL of saturated NaHCO3 was added with vigorous stirring. The organic layer was removed, washed with on 2 mL portion of water, dried (MgSO4), and concentrated in vacuo to give a residue which was crystallized from toluene-hexane, affording 0.36 g (71% yield) of 2-(4-methylphenyl)-1-phenylsulfonyl-1,1,2-trifluoroethane; mp 80°-82° C.; IR (KBr) 2924, 1447, 1352, 1185, 1163, 1117, 1054, 1013, 787, 757, 720, 686, 603, 567, 533, cm-1 ; 1H NMR (CDCl3) δ 2.36 (s, 3H), 6.10 (ddd, 1H, JHF =44, 18, 5 Hz), 7.16-8.07 (m, 9H); 19F NMR (CDCl3, relative to CFCl3) -44.0 ppm (dt, 1F J=44, 16 Hz), -109.3 ppm (dd, 1F, J=247, 15 Hz), -118.8 ppm (dt, 1F, J=248, 17 Hz); mass spectrum (70 eV) m/e (relative intensity) 314 (11, M+), 172 (41), 123 (100), 77 (31). Anal. Calcd. for C15H13F3O2S: C, 57.32; H, 4.17. Found: C, 56.90; H, 4.47.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[C:24]3[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]=3[CH:18]=[N:17][CH:16]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]3[C:24]=2[CH2:23][CH2:22][N+:21]([O-:34])([CH3:25])[CH2:20]3)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Solvent: ClCCl
Product: C[N+]1([O-])CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (12 mg, 0.03516 mmol) in DCM (2 mL) was added mCPBA (5.764 mg, 0.03340 mmol) and the mixture was stirred at RT for 2 h before the solvent was removed in vacuo. The residue was purified by FractionLynx to yield 5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine 2-oxide. MS (ES+) 358.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:14]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:14]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
N-t-butyloxycarbonylglycine (21.02 g, 120 mmole), L-proline benzylester hydrochloride (29.01 g, 120 mmole) and HOBt (1.62 g, 12 mmole) were dissolved in methylene chloride (400 ml), and triethylamine (12.14 g, 120 mmole) and WSC hydrochloride (23.00 g, 120 mmole) were added to the solution at -30° C. The mixture was stirred for 2 hours at less than 0° C., and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-t-butyloxycarbonylglycyl-l-proline benzylester(yield 42.50 g, 97.7%).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]([F:12])([C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])[CH2:3][O:4][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)F)cc1
Yield: 9.6 %

Procedure:
Following the above procedure, a solution of 2,2,3,3,4,4,4-heptafluoro-1-butanol (750 μL, 6 mmol) in N,N-dimethylformamide (8 mL) and 4-fluorobenzaldehyde (429 μL, 4 mmol) were reacted together with sodium hydride (288 mg as 55-60% mineral oil dispersion, 6 mmol) in N,N-dimethylformamide (2 mL). Flash chromatography gave 117 mg of 4-(2,2,3,3,4,4,4-heptafluorobutoxy)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.89 (d, 2H), 7.08 (d, 2H), 4.54 (tt, 2H) ppm.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:68]=[CH:67][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([CH:57]5[CH2:62][CH2:61][CH2:60][CH:59]([C:63]([O:65]C)=[O:64])[CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:68]=[CH:67][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([CH:57]5[CH2:62][CH2:61][CH2:60][CH:59]([C:63]([OH:65])=[O:64])[CH2:58]5)[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)C1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2CCCC(C(=O)O)C2)C3)cc1)c1ccc(Cl)cc1
Yield: 85 %

Procedure:
The compound of example 549 was prepared analogous to compound of example 98 by hydrolysis of compound of example 548.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[CH:8]=[CH2:9].Br[CH2:12][C:13]#[C:14][CH3:15].[Na].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([O:10][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]=[CH2:9])=[N:6][CH:5]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCBr
Reactant: C=Cc1ncc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=Cc1ncc(OCC#CC)cc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A reaction mixture of 5-methyl-6-vinylpyridin-3-ol (100 mg, 0.00074 mmol), sodium 1-bromobut-2-yne (118 mg, 0.00088 mol, Alfa-Aesar) and cesium carbonate (361 mg, 0.0011 mol) in DMF (2 mL) was stirred for 2 h at 80° C. After completion of the reaction, reaction mixture was cooled to ambient temperature, poured into ice-cold water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel and eluting with 0-10% ethyl acetate in petroleum ether to give 5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine as an off white solid (85 mg, 61.5%). MS m/z=188.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2-chloro-5-nitro-phenyl)-5-phenyl-1H-imidazole (430 mg, 1.43 mmol) and tin (II) chloride dihydrate (1.15 g, 5.02 mmol) in EtOH (15 ml) is heated at reflux for 3 hours. The mixture is cooled down to room temperature and the solvent is removed in vacuo. The residue obtained is treated with ethyl acetate (80 ml) and 1N NaOH solution is added until the pH is raised to around 12. The suspension is kept stirring for 10 minutes and then filtered through Celite cake. The solution obtained is concentrated to yield 4-chloro-3-(5-phenyl-1H-imidazol-2-yl)-phenylamine as a dark red foam-like solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)=[O:25])=[CH:22][CH2:23][C:12]3=[CH:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH3:47].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH3:47]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2C=C3CC=C(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)N3Cc3ccccc32)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC4CCCNC4)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
To a solution of tert-butyl 3-{[({10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]methyl}piperidine-1-carboxylate of Step A (0.42 g, 0.66 mmol) in dry dichloromethane (3 mL) was added trifluoroacetic acid (0.51 mL, 6.6 mmol) and the reaction mixture stirred at room temperature under nitrogen for 20 hours. The reaction mixture was then diluted with dichloromethane (50 mL), washed with 1 M sodium hydroxide solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a pink glass. Purification by flash chromatography using a solvent gradient of 2.5 to 10% ammonia saturated methanol in dichloromethane gave a pale yellow oil (0.31 g). Crystallization from diethyl ether (2 mL) afforded the title compound (0.19 g) as a pale yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:30]([CH3:32])[CH3:31])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][O:8]C(=O)C)(=O)C.CO.C[O-].[Na+]>CO>[CH3:32][N:30]([C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:7][OH:8])[CH2:5][OH:4])[CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC(CO)(CO)N(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound (436 mg) of (1) above was dissolved in 15 ml of methanol and 37 mg of a 28% sodium methoxide methanol solution was added thereto. The mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and water was added thereto. The resultant precipitate was collected by filtration and recrystallized from chloroform-hexane to give 295 mg of colorless, crystalline 2-(N,N-dimethylamino)-2-octadecyl-1,3-propanediol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: C=Cc1cccc(N)c1
Reaction time: 5 h
Yield: 92.6 %

Procedure:
50 g of 3-nitrostyrene are dissolved in 240 g of methanol. 10 g of an 18% strength suspension of CoS3 in methanol are added to the solution. The mixture is heated to 100° C in the presence of 30 bars of H2 in a stainless steel autoclave. After 5 hours, the absorption of hydrogen is complete. The mixture is heated for a further half hour to 110° C at 30 bars of H2. 0.5 g of tert.-butyl-pyrocatechol is added to the cooled contents of the autoclave, the mixture is filtered and the solvent is distilled off. 37 g of 3-aminostyrene are obtained. Boiling point16 = 113° -115° C, ND20 = 1.6102.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([C:21]([OH:24])([CH3:23])[CH3:22])[C:13]([NH:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:14])=O)(C)(C)C.Cl.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([OH:51])=O)[CH2:43][C:44]1[N:45]=[CH:46][S:47][CH:48]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([NH:8][C@@H:9]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([C:21]([OH:24])([CH3:22])[CH3:23])[C:13]([NH:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:14])=[O:51])[CH2:43][C:44]1[N:45]=[CH:46][S:47][CH:48]=1)=[O:40])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A mixture of 530 mg (1.16 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methylbutyl]hexanamide (prepared as described in Preparation 7) in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. This operation was repeated in total three times, and then the residue was dried under vacuum for 8 hours. The dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and then 350 mg (1.29 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. Subsequently, 0.21 ml (1.38 mmoles) of 95% diethyl cyanophosphate (i.e. diethyl cyanophosphate of purity about 95%) and 0.36 ml (2.58 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling, and under an atmosphere of nitrogen. The mixture was stirred for 6 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), to give 650 mg (yield 92%) of the title compound as white crystals, melting at 190°-193° C.