Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43]>CS(C)=O>[C:7]([S:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)c2c(CCCCCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21

Procedure:
Triphenylmethanethiol (11.90 g, 43.08 mmol) was suspended in DMSO (40 mL). DBU (7.41 mL, 49.55 mmol) and 6-bromohexylphthalimide (13.32 g, 42.94 mmol) were added, and the mixture was allowed to react for approximately 15 min. The reaction mixture was partitioned between ethyl acetate (700 mL) and 0.1 M HCl (200 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic fractions were washed with NaHCO3 sat. (80 mL) and brine (80 mL), dried over MgSO4, filtered and concentrated. The crude yellow oil was recrystallized from n-heptane/ethyl acetate. The intermediate 6-(S-Trityl-)mercaptohexylphthalimide was obtained as a white solid (13.3 g, 26.4 mmol, 62%).
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].Cl.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:1][CH2:2][OH:3])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: OCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 78.6 %

Procedure:
Ethylene bromohydrin (5.4 g) was added dropwise to a mixture of 1-(3-chlorophenyl)piperazine hydrochloride (5 g), potassium carbonate powder (12 g) and N,N-dimethylformamide (35 ml) with stirring. The mixture was further stirred at room temperature overnight, then diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: ethyl acetate-methanol (4:1)] to give 4.06 g (78.6%) of 4-(3-chlorophenyl)-1-piperazineethanol as an oil.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:15][N+:14]=1[O-])(=[O:10])[CH3:9].C(=O)(O)[O-].[Na+]>>[C:8]([O:11][CH:12]([O:4][C:1](=[O:3])[CH3:2])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:15][N:14]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCCOc1ccc(COC(C)=O)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCCOc1ccc(C(OC(C)=O)OC(C)=O)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5 ml (53.00 mmol) of acetic anhydride are added to 0.83 g of the crude product from example 26A, and without further solvent the mixture is stirred at +120° C. for 3 h. The reaction mixture is then cooled to 0° C., and 2 ml of saturated aqueous sodium bicarbonate solution are added. The aqueous phase is extracted twice with in each case 5 ml of dichloromethane, and the combined organic phases are dried over magnesium sulphate. After removal of the solvent, the crude product is used without further purification for the subsequent reaction.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][O:12][CH3:13].[Si:14]([O:21][CH2:22][CH:23]([OH:38])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:21][CH2:22][CH:23]([O:38][CH2:11][O:12][CH3:13])[CH2:24][N:25]1[C:30](=[O:31])[CH:29]=[N:28][C:27]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[N:35][C:26]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COCCl
Reactant: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)cnc2ccc(OC)nc21
Reaction time: 24 h
Yield: 67.3 %

Procedure:
N,N-Diisopropylethylamine (1.93 ml, 11.10 mmol) and chloromethylmethyl ether (0.56 ml, 7.40 mmol) were added under cooling on ice to a solution of 4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.35 g, 3.70 mmol) in dichloromethane (20 ml) and the mixture was stirred for 24 hours. The reaction solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 1.02 g (67%) of the title compound in the form of a yellow oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.[Br:33][C:34]1[N:35]=[C:36]([CH:58]=[O:59])[N:37]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=1>C1COCC1>[Br:33][C:34]1[N:35]=[C:36]([CH:58]([C:5]2[C:6]([F:15])=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[OH:59])[N:37]([C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=1
Reactant: CCc1ccc(F)c(-c2ccccc2)c1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccccc2)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -40 °C
Yield: 74.1 %

Procedure:
To a solution of Intermediate 228.2 (85 mg, 0.424 mmol) and PMDTA (0.10 mL, 0.478 mmol) in 4 ml THF at −78° C., was added BuLi (1.4 M in hexanes, 0.334 mL, 0.467 mmol). The mixture was stirred with warming to −40° C. over 30 min, recooled to −78° C., then a solution of Intermediate 175.1 (177 mg, 0.424 mmol) in 1.5 mL THF was added. The mixture was warmed to rt over 0.5 h. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 194 mg of Intermediate 228.3 as a colorless solid.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1.COC(OC)(C)C>CO>[C:1]([O:13][CH3:14])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Solvent: COC(C)(C)OC
Solvent: CO
Product: COC(=O)/C=C/c1ccc(O)c(O)c1
Yield: 98 %

Procedure:
Put a 10 g caffeic acid (1) in a reaction bottle, and add 1 g TsOH and 3 ml 2,2-dimethoxypropane and 10 ml methanol thereinto, followed by refluxing for 6 hours. After the refluxation, remove the solvent and pour the resultant solution into 100 ml water, followed by being extracted by the ethyl acetate for three times, neutralizing with 3% NaHCO3, and finally performing a column chromatography. Therefore, the product, methyl caffeate (the compound 2) is obtained with 98% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:15]2)=[CH:10][CH:9]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:54].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH3:54][O:50][C:49](=[O:51])[CH2:48][CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:52])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:38])=[O:39]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
To a solution of 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid in 5 ml of MeOH at 0° C. are added 5.0 mmol of TMS-diazomethane (2M in hexane) until the conversion to the methyl ester is complete. The reaction mixture is treated with magnesium sulfate to destroy the excess of TMS-diazomethane. The solids are removed by filtration and the organic layer is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:16](=[O:18])=[O:17].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([F:13])[C:12]=1[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: COc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.0M in hexane; 25.0 ml, 0.25 mol) was added dropwise to a stirred, cooled (-78° C.) solution of 3,5-difluoroanisole (35.9 g, 0.25 mol) in dry THF (200 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured into a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide (twice), the combined basic extracts were acidified with 36% hydrochloric acid, and the product was extracted into ether (twice), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a colourless solid.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])C[CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)C2.C1(CCCO)CCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH2:35][CH2:36][CH:37]2[CH2:43][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCCCC1CCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-cyclohexylpropan-1-ol, the title compound was obtained as a colorless solid (0.03 g, 7%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 4.12 (t, J=6.2 Hz, 2H), 2.87 (s, 6H), 1.80-1.58 (m, 7H), 1.35-1.11 (m, 6H), 0.94-0.88 (m, 2H); MS (ES−) m/z 419.2, 421.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]([OH:26])[C:24]#[CH:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:25]#[C:24][CH:23]([C:15]2[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[OH:26])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(O)C#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (444 mg) as per the general procedure to afford 3-(2,4-Diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-yn-1-ol as a yellow powder (275 mg, 80%): Rf=0.12 (9:1, CHCl3:MeOH); mp=174-176° C.; 1H NMR (DMSO-d6) δ 6.85 (s, 2H), 6.27 (s, 2H), 5.98 (d, J) 5.6 Hz, 1H), 5.53 (d, J) 5.4 Hz, 1H), 3.78 (s, 6H), 3.65 (s, 3H), 2.19 (s, 3H), 1.51 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 167.1, 164.3, 161.2, 152.7, 138.3, 136.7, 103.7, 99.1, 87.9, 79.5, 63.6, 60.0, 55.8, 22.5; HRFAB[M+Li]351.1638 (calculated C17H20N4O4Li: 351.1645).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:16][O:15]2)=[CH:8][CH:7]=1.N1C=[C-]N=N1.[Na+].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.[H-].[Na+]>CN(C)C=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:14]([CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1)([OH:15])[CH2:16][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(C=Cc2ccc(C3OCCO3)cc2)CO1
Agent: [H-]
Agent: [Na+]
Agent: [c-]1c[nH]nn1
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(C=Cc1ccc(C2OCCO2)cc1)Cn1cncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.3 %

Procedure:
25.6 g (0.093 mol) of 2-{2-[4-(1,3-dioxolan-2-yl)-phenyl]-ethenyl}-2-tert.-butyl-oxirane in 47 ml of absolute dimethylformamide are added dropwise, at room temperature, to a solution of sodium triazolide, prepared by slowly introducing 12.9 g (0.187 mol) of 1,2,4-triazole into a suspension of 5.6 g (0.187 mol) of sodium hydride (80% strength in paraffin oil) in 187 ml of absolute dimethylformamide. The reaction mixture is stirred at 80° C. for 4 hours and left to stand overnight at room temperature. Thereafter, the reaction mixture is poured onto ice water and extracted several times with ethyl acetate. The combined ethyl acetate phases are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed over a silica gel column (methylene chloride/ethyl acetate=2:1) and the product is recrystallized from n-hexane/ethyl acetate. 7.75 g (24% of theory) of 3,3-dimethyl-2-{2-[4-(1,3-dioxolan-2-yl)-phenyl]-ethenyl}-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 109.5°-110° C. are obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32](Cl)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([SH:51])=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([S:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(Cl)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Sc2ccnc3c2c2cc(-c4ccc(N5CCN(C)CC5)cc4)ccc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 9-Benzenesulfonyl-4-chloro-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-9H-pyrido[2,3-b]indole (Building block A) (60 mg) in DMF (1.2 mL), under Argon, K2CO3 (56 mg, 3.5 equiv.) and 4-methoxythiophenol (0.029 mL, 2 equiv.) were added. After stirring for 0.5 h at r.t., the reaction mixture was diluted with AcOEt (20 mL), washed with sat. aqueous NH4Cl (20 mL) and brine (20 mL) The organic layer was dried over MgSO4, filtered and evaporated to dryness. The trituration procedure afforded the desired compound in 72% yield as a beige solid. 1H-NMR (300 MHz, CDCl3) δ=8.55 (d, J=8.8 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.18-8.09 (m, 2H), 7.77 (dd, J=8.8, 1.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.57-7.48 (m, 3H), 7.45-7.35 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.53 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.47-3.33 (m, 4H), 2.90-2.74 (m, 4H), 2.51 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ=161.4 (C), 150.7 (C), 150.6 (C), 147.7 (C), 146.0 (CH), 138.8 (C), 137.7 (2 CH), 137.1 (C), 136.0 (C), 134.0 (CH), 131.9 (C), 129.0 (2 CH), 128.0 (2 CH), 127.6 (2 CH), 126.5 (CH), 123.8 (C), 121.5 (CH), 118.2 (C), 116.3 (2 CH), 115.8 (2 CH), 115.1 (CH), 114.8 (CH), 114.6 (C), 55.5 (CH3), 55.1 (2 CH2), 48.8 (2 CH2), 46.2 (CH3). ESI-MS: m/z 621.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH2:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[NH2:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:3]=1[NH:4][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(N)c(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Temperature: 45 °C

Procedure:
0.15 mol (25.05 g) of 2-amino-3-nitro-5-methylaniline is dissolved in 75 ml of pyridine, and 0.165 mol (31.4 g) of para-toluenesulphonyl chloride is then added gradually, whilst stirring, at between 40° and 45° C. When the addition has ended, the stirring is maintained for 1 hour at 45° C., the reaction medium is then poured into 450 ml of iced water and ther pyridine is neutralised with the aid of hydrochloric acid. The expected product which has precipitated is filtered off, washed with water and then recrystallised from acetic acid. After drying in vacuo, it melts at 184° C.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][CH:20]=[CH2:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)C=[O:26]>O.[Pd](Cl)Cl>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:26])[CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
A suspension of 500 mg (5 mmoles) of cuprous chloride and 180 mg (1 mmole) of palladium chloride in a mixture of 5 ml of dimethylformamide and 0.6 ml of water was stirred for 1 hour under an atmosphere of oxygen. At the end of this time, 1.41 g(5.03 mmoles) of benzyl 2(S)-benzyl-4-pentenoate (prepared as described in Preparation 18) was added to the mixture. The mixture was then stirred for an additional 5 hours at room temperature and under an atmosphere of oxygen, after which the reaction mixture was poured into 100 ml of 1N aqueous hydrochloric acid, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 5:1 by volume mixture of hexane and ethyl acetate as eluent), to give 1.28 g (yield 86%) of the title compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>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.[Cu]I.C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:3]1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)c(C#Cc1ccccc1)nn2C1CCCCO1
Yield: 76.2 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.31 mmol), 10.0 mL of acetonitrile (CH3CN), diisopropylethylamine (172 mg, 1.33 mmol, 1.01 equiv.), dichlorobis(triphenylphosphine)palladium(II) [(Ph3)P2PdCl2, 0.0187 mmol, 0.0143 equiv.), copper (I) iodide (CuI, 13.1 mg, 0.0688 mmol, 0.0525 equiv.), and phenylacetylene (147 mg, 1.44 mmol, 1.10 equiv.) were refluxed for 3 h and concentrated. Purification by silica gel chromatography using 20–30% EtOAc in hexanes afforded the title compound (327 mg, 76.2% yield): ES-MS (m/z) 328 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:12]=[O:13].CC([O-])(C)C.[K+]>CS(C)=O.C(O)(C)(C)C>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]([CH3:2])[CH2:12][OH:13])([O-:11])=[O:10]
Reactant: C=O
Reactant: CCc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(CO)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-Ethyl-2-nitrobenzene (13.5 mL, 100 mmol) was dissolved in dimethylsulfoxide (100 mL). Paraformaldehyde (4.50 g, 150 mmol) and KOtBu (2.81 g, 25 mmol) in t-butyl alcohol (30 mL) were added and the mixture was stirred at room temperature for 3 h. The solution was washed with a molar solution of HCl (25 mL), followed by brine (3×100 mL). All the aqueous layers were combined and extracted with ethyl acetate (3×100 mL). The organic portion was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude product was purified on a silica gel column. Elution of the column with 20-30% ethyl acetate in hexanes gave 16.12 g (89 mmol, 89% yield) of 2-(2-nitrophenyl)propanol. 1H-NMR (600 MHz, DMSO-d6): δ 7.75 (d, J=8.10 Hz, 1H, Ar—H), 7.63 (t, J=7.62 Hz, 1H, Ar—H), 7.58 (d, J=7.80 Hz, 1H, Ar—H), 7.42 (t, J=7.50, 1H, Ar—H), 4.73 (t, J=5.30 Hz, 1H, OH), 3.50 (m, 2H, CH2), 3.19 (m, 1H, CH), 1.21 (d, J=6.90 Hz, 3H, CH3). TLC: 20% ethyl acetate in hexane, Rf=0.3.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[C:28]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)[CH:23]=[CH:24][C:25]=1[O:31][CH3:32]
Reactant: COc1ccc(Br)cc1OC
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1OC
Yield: 31.9 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-1,2-dimethoxybenzene (326 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 131 mg (yield 32%).