Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:18])[C:9]=2[CH:8]=1)(=O)=O.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:10]1([CH3:19])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:22]=[CH2:23])[CH:8]=2)[C:13](=[O:17])[CH2:12][CH2:11]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CCC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)C(C)(C)CCC2=O
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a solution of 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (Preparation 1B, 0.443 g, 1.37 mmol) in dioxane (2.5 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.444 mL, 1.51 mmol) and lithium chloride (0.175 g, 4.12 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (2×). To the mixture was added tetrakis(triphenylphosphine) palladium(0) (0.159 g, 0.137 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred at room temperature overnight. The reaction mixture was filtered under reduced pressure, and the solid was rinsed with ethyl acetate (˜50 mL total). The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with ether (˜25 mL). The resulting solid was removed by vacuum filtration and rinsed with ether (˜25 mL). The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-10%) to give 4,4-dimethyl-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (0.201 g, 1.00 mmol, 73. % yield) as a colorless oil. The product had an HPLC ret. time=2.55 min. (condition A); LC/MS M+1=200.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](Cl)=[O:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].CCN(CC)CC.Cl.[CH3:38][O:39][NH:40][CH3:41]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:38][O:39][N:40]([CH3:41])[C:13]([C:10]1[C:11]([CH3:12])=[C:5]2[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[C:3]([C:1]#[N:2])[CH:8]=[N:7][N:6]2[CH:9]=1)=[O:14]
Reactant: CNOC
Reactant: Cc1c(C(=O)Cl)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl chloride (Example 412B) (181 mg, 0.45 mmol) in CH2Cl2 (3 ml) was added Et3N (160 μl, 1.13 mmol) followed by O,N-dimethylhydroxyamine hydrochloride (44 mg, 0.45 mmol) in one portion. The mixture was stirred overnight, diluted with CHCl3 (20 ml), washed with water (2×20 ml), dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (138 mg, 72%) (50% EtOAc—hexanes). It has a retention time of 6.45 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=428.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24]CC3C=CC=CC=3)[CH:17]=2)=[O:14])=[CH:11][C:10]=1[O:34]C)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CN(C)C=O.CO.[Pd]>[OH:34][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:9]=1[O:8][CH3:1])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)=[O:14]
Reactant: COc1cc(C(=O)Nc2ccc(OC)c(OCc3ccccc3)c2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(O)c2)cc1O
Yield: 40.2 %

Procedure:
A solution of the 4-Benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide (1.05 g) in a mixture of N,N-dimethylformamide/methanol (1:5, 120 ml) was hydrogenated in presence of 10% palladium on carbon at 40 Psi at room temperature for 12 hrs. Removal of the catalyst by filtration and purification by flash chromatography over silica gel eluting with 65% ethyl acetate/hexane provided 0.26 g of 3-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-4-methoxybenzamide. Yield=41.6%
Reaction SMILES: FC(F)(F)C([O-])=O.ClC1C=C2C(=O)NC=C(CC3C=CC(F)=C(C=3)C(N3CCC[NH2+]CC3)=O)N2C=1.[Cl:36][C:37]1[CH:38]=[C:39]([C:42]([O:44]N2C(=O)CCC2=O)=O)[NH:40][CH:41]=1.[CH3:52][O:53][C:54]1[CH:86]=[C:85]([O:87][CH3:88])[CH:84]=[CH:83][C:55]=1[CH2:56][NH:57][CH2:58][C:59]#[C:60][C:61]1[CH:66]=[CH:65][N:64]=[C:63]([C:67]([N:69]2[CH2:75][CH2:74][CH2:73][N:72]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[CH2:71][CH2:70]2)=[O:68])[CH:62]=1.C([O-])(O)=O.[Na+]>CC#N.O>[Cl:36][C:37]1[CH:38]=[C:39]([C:42]([N:57]([CH2:56][C:55]2[CH:83]=[CH:84][C:85]([O:87][CH3:88])=[CH:86][C:54]=2[O:53][CH3:52])[CH2:58][C:59]#[C:60][C:61]2[CH:66]=[CH:65][N:64]=[C:63]([C:67]([N:69]3[CH2:75][CH2:74][CH2:73][N:72]([C:76]([O:78][C:79]([CH3:82])([CH3:80])[CH3:81])=[O:77])[CH2:71][CH2:70]3)=[O:68])[CH:62]=2)=[O:44])[NH:40][CH:41]=1
Reactant: COc1ccc(CNCC#Cc2ccnc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2)c(OC)c1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Cl)c[nH]1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Agent: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)cn23)ccc1F)N1CCC[NH2+]CC1
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN(CC#Cc2ccnc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2)C(=O)c2cc(Cl)c[nH]2)c(OC)c1

Procedure:
A solution of Example 6, F1 (2 eq), I2 (1 eq) and NaHCO3 (2.5 eq) in a mixture of CH3CN and H2O (20:1) was heated at reflux for 12 hrs and then the MeCN was removed under reduced pressure. The resulting residue was partitioned between DCM and water. The organic phase was washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure. The resulting brown oil was purified by Biotage system eluting with EtOAc/petroleum ether to obtain the desired compound. MS (ES) C33H38ClN5O6 requires: 635, found: 636 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]#[N:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(COC1C=C(N[S:24]([CH3:27])(=[O:26])=[O:25])C=CC=1)#N.NC1C=C(C=CC=1)OCC#N>>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([NH:1][S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=[C:4]([CH2:10][C:11]#[N:12])[CH:5]=1
Reactant: CS(=O)(=O)Nc1cccc(OCC#N)c1
Reactant: Cc1c(N)cc(CC#N)cc1Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(Cl)cc(CC#N)cc1NS(C)(=O)=O

Procedure:
N-(3-chloro-5-cyanomethyl-2-methylphenyl) methanesulfonamide was prepared from (3-amino-5-chloro-4-methylphenyl) acetonitrile in a manner similar to that described in Example 1 for the preparation of N-(3-cyanomethoxyphenyl)-methanesulfonamide from (3-aminophenoxy)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[C:25]5=[O:33])[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].[H-].[Na+].O>C1COCC1.C(Cl)Cl>[CH3:34][C:19]1[C:20]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:33])=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N5CCCC5=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.5 %

Procedure:
A solution of 7-amino-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 54-14, 60 mg, 0.134 mmol) in THF (3 mL) was treated with TEA (0.019 mL, 0.134 mmol) and a solution of 4-bromobutanoyl chloride (24.92 mg, 0.134 mmol) in DCM (1 mL). The mixture was stirred at rt for 40 min, then was diluted with DCM, washed with water, dried and concentrated. The residue was dissolved in THF (5 mL) and added to a suspension of sodium hydride (60% oil dispersion, 40 mg, 1.000 mmol, pre-washed with hexane) in THF (5 mL). The mixture was stirred at rt overnight, then was heated at 65° C. for 30 min. The mixture was cooled to rt, poured into water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 99:0.9:0.1 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide (50 mg, 66%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 10.67 (1H, s), 7.96 (1H, d, J=7.47 Hz), 7.91 (1H, s), 7.74 (1H, d, J=7.91 Hz), 7.62-7.67 (1H, m), 7.52-7.58 (2H, m), 7.45-7.48 (2H, m), 7.38-7.42 (1H, m), 7.22 (1H, dd, J=8.79, 1.76 Hz), 7.11 (2H, d, J=7.91 Hz), 4.86 (2H, s), 3.90-4.02 (2H, m), 2.66 (2H, t, J=8.13 Hz), 2.16-2.25 (2H, m), 1.94 (3H, s). Mass spectrum m/z 515.3 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])=[C:20](\O)/[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC.C(Cl)Cl>[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=[CH2:21])[CH3:3])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1

Procedure:
A distilled solution of diazomethane in ether (containing 1.3 mM of diazomethane) is added to a solution of crude 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester, obtained by ozonisation of 681 mg (1.0 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester, in 5 ml of methylene chloride at 0° C. The mixture is stirred for one hour at 0° C. and washed with water, and the organic layer is dried over sodium sulphate. The solvents are removed in vacuo and the residue is chromatographed on 35 g of acid-washed silica gel, using toluene/ethyl acetate, 2:1. An isomer mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester is obtained. IR spectrum (in CH2Cl2): 5.60, 5.88, 6.67, 9.15 and 9.92 μ.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:20])(=[O:19])[N:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:19])(=[O:20])[N:16]([CH3:17])[CH3:18])[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A solution of 660 mg (1.19 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-dimethylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (30 mL) was treated with EtOH (600 μL) and TFA (3 mL) and stirred at RT for 24 h. MeOH (20 mL) was added, and the solvents were evaporated in vacuo. The solid was triturated with acetonitrile to afford 342 mg (67%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 8.20-8.09 (m, 1H), 7.92 (s, 1H), 7.24-7.16 (m, 1H), 7.13 (s, 1H), 5.84-5.75 (m, 1H), 3.30-3.19 (m, 4H), 3.08-2.96 (m, 2H), 2.82 (s, 6H), 2.29-2.17 (m, 4H), 1.85-1.68 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H25N5O3S, 428.2 (M+H). found 428.1.
Reaction SMILES: C(O[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[N:12]([CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:13](=[O:32])[CH2:14][C:15]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=2[S:17](=[O:31])(=[O:30])[N:16]=1)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH3:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][N:12]1[C:13](=[O:32])[C:14]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)=[C:4]([OH:5])[CH:6]2[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCC21
Temperature: 60 °C
Reaction time: 13 h
Yield: 34.6 %

Procedure:
To a solution of cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclohexanecarboxylic acid ethyl ester (138.7 mg, 0.243 mmol) in absolute ethanol (10 mL) was added a 21% w/w solution of sodium ethoxide in ethanol (0.91 mL, 2.44 mmol). After stirring at 60° C. for 13 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-100% ethyl acetate in hexanes) to afford the desired product, N-{3-[2-(3,3-dimethylbutyl)-5-hydroxy-3-oxo-2-aza-bicyclo[4.4.0]dec-4-en-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (44.3 mg, 0.084 mmol, 35%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (9H, s), 1.10-1.87 (9H, m), 2.32 (1H, bs), 3.04 (3H, s), 2.92-3.82 (4H, m), 7.47-7.58 (3H, m), 10.13 (1H, bs). LC-MS (ESI) calcd for C23H32N4O6S2 524.18, found 525.3 [M+H+]. Anal. calcd for C23H32N4O6S2: C, 52.65; H, 6.15; N, 10.68; S, 12.22, found C, 52.56; H, 6.10; N, 10.71; S, 12.16.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:14])(=O)=O>>[Cl:14][CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cl)C(=O)CC
Reaction time: 16 h

Procedure:
Ethyl 3-oxopentanoate, 20.0 grams (0.175 mole), was stirred at ambient temperature, and 23.6 grams (0.175 mole) of sulfuryl chloride was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was stirred for about 16 hours. The reaction mixture was then distilled under reduced pressure, yielding 23.3 grams of ethyl 2-chloro-3-oxopentanoate; bp 100°-103° C. at 21 mm.
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)[CH2:3][CH:4]=[CH2:5].[N+](=[CH2:20])=[N-].O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C@H:6]([CH:2]([OH:1])[CH2:3][CH:4]2[CH2:20][CH2:5]2)[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(O)CC2CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
Add palladium (II) acetate (50.0 mg; 0.22 mmol) to a stirred solution of (3S)-tert-butyl 3-(1-hydroxybut-3-enyl)pyrrolidine-1-carboxylate (S-mix) (3.0 g, 12.43 mmol) and freshly prepared diazomethane (50 mL, about 23.8 mmol in diethyl ether) in THF (20 mL) under nitrogen at 0° C. (Caution: vigorous gas evolution). Stir at 0° C. for 10 minutes. Warm to room temperature, pour into water and extract with ethyl acetate (3×). Wash the combined organics with water and brine. Dry (MgSO4), filter and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to afford 2.9 g (91%) of the title compound. MS (m/z)=200.0 (M−55)
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH:35]=O)[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH2:35][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (2.74 ml) in tetrahydrofuran (50 ml), sodium hydride (60%, oily, 552 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-carbaldehyde (6.31 g) in tetrahydrofuran (100 ml) was added slowly, and the solution was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, and ethyl 3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]propionate (6.79 g, yield: 95%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:16]=[CH:15][N:14]=[C:13]2O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>CN(C)C=O>[C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:16]=[CH:15][N:14]=[C:13]2[Cl:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(COc2cc3ncnc(O)c3cc2OC(=O)c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CCC(COc2cc3ncnc(Cl)c3cc2OC(=O)c2ccccc2)CC1
Yield: 94 %

Procedure:
A mixture of 4-hydroxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl benzoate (0.215 g, 0.55 mmol), thionyl chloride (2 ml) and dimethylformamide (0.05 ml) were refluxed for 15 minutes. The solvent was evaporated in vacuo to yield 4-chloro-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl benzoate (0.250 g, 94% yield) as the hydrochloride salt:
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CO>[CH3:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]3[N:30]=[C:15]([C:5]4[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]5[CH2:14][CH2:13][CH2:12][CH2:11][O:10]5)[N:6]=4)[NH:31][C:26]=3[CH:25]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])[nH]c3c2)CC1
Temperature: 22 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
742 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde are added to a solution of 680 mg of 4-(4-methylpiperazino)-1,2-benzenediamine in 30 mL of methanol. The reaction medium is stirred at 22° C. for 3 hours. The reaction medium is heated at 60° C. using an oil bath for 1H30, and then stirred at 22° C. for 64 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in dichloromethane containing 10% methanol. 370 mg of 6-(4-methylpiperazin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole are isolated. Analytical LC/MS: tr=1.88 min; [M+H]+=412.32; ELSD=97%; DAD=93%. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.50 to 2.23 (m, 6H); 2.25 (s, 3H); 2.50 (m masked, 4H); 3.14 (m, 4H); 3.70 (m, 1H); 4.00 (m, 1H); 5.59 (broad d, J=9.5 Hz, 1H); from 6.90 to 7.15 (m, 2H); from 7.39 to 7.54 (m, 1H); 9.17 (s, 1H); from 12.5 to 12.7 (m, 1H).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][CH:8]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[NH4+].[Cl-]>C1COCC1.O>[CH2:16]([O:15][C:14](=[O:18])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:13])[N:12]=1)[CH3:17]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(Cl)n1
Reaction time: 0.75 h
Yield: 60 %

Procedure:
To a solution of n-BuLi (100 mL, 250 mmol of a 2.5 M solution in hexanes) in THF (200 mL) was added DIA (36 mL, 255 mmol) at 0° C. After stirring for 45 min, 6-methyl-2-chloropyridine (14.2 g, 111 mmol) was added slowly, maintaining the temperature <5° C. After 30 min, diethyl carbonate (30 mL, 250 mmol) was added dropwise maintaining the temperature below 10° C. The solution was stirred at 0° C. for 1 h, then water was slowly added, followed by the addition of a saturated solution of NH4Cl. The organic phase was dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified through a pad of silica gel to give the product (13.3 g, 66.6 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 2.04 (s, 2H), 4.19 (q, 2H), 7.23 (dd, 2H), 7.62 (t, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][C:24]=1[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:4][CH:3]=2)[N:20]=1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(c2nc(COc3ccc(CCCCn4cncn4)cc3)co2)CCc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
A mixture of 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (450 mg), 4-chloromethyl-2-(3,4-dihydro-2-naphthyl) oxazole (565 mg), potassium carbonate (290 mg) and N,N-dimethylformamide (10 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with chloroform-methanol (50:1, v/v) was recrystallized from ethyl acetate-hexane to give 1-[4-[4-[2-(3,4-dihydro-2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole as colorless prisms, mp 96-97° C. The yield was 49%.