Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([O:38][N:39]=[C:40]([C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)[C:41](O)=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:69][CH:70]1[C:95](=[O:96])[N:72]2[C:73]([C:79]([O:81][CH:82]([C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=3)[C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)=[O:80])=[C:74]([CH2:77][Cl:78])[CH2:75][S:76][C@H:71]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.Cl>C(Cl)Cl>[CH:1]([O:14][C:15]([CH:17]([O:38][N:39]=[C:40]([C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[S:47][CH:48]=1)[C:41]([NH:69][CH:70]1[C:95](=[O:96])[N:72]2[C:73]([C:79]([O:81][CH:82]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:89]3[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=3)=[O:80])=[C:74]([CH2:77][Cl:78])[CH2:75][S:76][C@H:71]12)=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:19]=1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: COCCOCOc1ccc(C(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OCOCCOC
Agent: Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COCCOCOc1ccc(C(ON=C(C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OCOCCOC
Reaction time: 1 h

Procedure:
4.87 g (5.19 mmol) of 2-[α-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 2.34 g (5.64 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 90 ml of methylene chloride, and 3.2 ml (25.4 mmol) of N,N-dimethylaniline and 0.63 ml (6.77 mmol) of phosphorus oxychloride were dropwise added at 0° C. The mixture was stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid, and extracted with 1N methylene chloride aqueous solution. The organic phase was washed with 1N sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain a crude benzhydryl 7-{2-[α-benzhydryloxycarbonyl-3,4-di(2-methoxyethoxymethoxy)benzyloxyimino]-2-(tritylaminothiazol-4-yl)acetamido}-3-chloromethyl-3-cephem-4-carboxylate (syn-isomer), which was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[CH:16][NH:17]3)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][NH:17]3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCCCCCOc2cccc3[nH]ccc23)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc(OCCCCCOc2cccc3c2CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of 4-[5-(4-chloro-phenoxy)-pentyloxy]-1H-indole (1.72 g, 5.2 mmol) in 20 mL acetic acid was added sodium cyanoborohydride (2.61 g, 41.6 mmol). After stirred overnight at room temperature, the reaction mixture was treated with saturated aqueous sodium bicarbonate solution (50 mL). The solution was then extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with brine, dried over MgSO4, and concentrated to give a crude product as a white solid. The crude product was purified by silica gel column chromatography to give 4-[5-(4-chloro-phenoxy)-pentyloxy]-2,3-dihydro-1H-indole (600 mg, 1.80 mmol, 35%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:39])[N:25]([CH2:33][CH2:34][CH2:35][C:36](=[O:38])[NH2:37])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:36]([CH2:35][CH2:34][CH2:33][N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:24](=[O:39])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)(=[O:38])[NH2:37]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)c2ccccc2F)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F

Procedure:
A solution of (2-{3-[(3-Carbamoyl-propyl)-(2-fluoro-phenyl)-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.030 g) in trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.009 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1>P([O-])([O-])([O-])=O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(NC(=O)CCC(=O)Nc1ccc(C=NN)cc1)C1CC1
Agent: O=P([O-])([O-])[O-]
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CC(=O)O)C2CC2)cc1
Reaction time: 20 h
Yield: 83 %

Procedure:
Porcine liver esterase (200 μL, Sigma, 11 mg/mL in 3.2 M (NH4)2SO4 at pH=8) was added to the final product of Example 28 in 20 mL of 0.1M phosphate buffer (pH=7.4). After 20 h at 23° C., the reaction mixture was concentrated in vacuo. The residue was dissolved in 1N HCl (3 mL) and subsequently diluted with acetonitrile (5 mL) followed by immediate purification by reverse phase HPLC using the conditions of Example 1 to afford 23.0 mg (83%) of the title compound. The product was verified by 13C NMR (CD3OD) δ 1.8, 2.6, 15.0, 30.3, 31.8, 39.1, 50.6, 119.2, 122.1, 128.6, 144.3, 166.8, 172.0, 172.4, 173.4; Fast Atom Bombardment Mass Spectrometry (MH+)=347.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:19][CH2:18][NH:17][CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8][C:7]=4[C:6]=3[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(Cl)cc1)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Yield: 104.4 %

Procedure:
The 7-nitroquinoxalinedione from Example 31 (100 mg, 0.38 mmol) was treated with the CDI adduct of 4-chlorobenzoic acid (0.57 mmol) by a procedure similar to that in Example 32 to give a yellow solid (159 mg, 99% yield). mp=280-283° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:17]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([N:29](CC3C=CC(OC)=CC=3OC)[C:30]3[S:34][N:33]=[CH:32][N:31]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[N:19]([CH3:46])[CH:18]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([NH:29][C:30]4[S:34][N:33]=[CH:32][N:31]=4)(=[O:27])=[O:28])=[CH:23][CH:24]=3)[N:19]([CH3:46])[CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: COc1ccc(B(O)O)c2ccccc12
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c2ccccc12

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-methoxynaphthalen-1-yl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(4-methoxynaphthalen-1-yl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.96 (s, 3 H) 4.02 (s, 3 H) 7.06 (d, J=8.02 Hz, 1 H) 7.32 (d, J=8.36 Hz, 1 H) 7.37-7.48 (m, 3 H) 7.51 (d, J=8.25 Hz, 1 H) 7.72 (s, 1 H) 7.84 (d, J=8.59 Hz, 1 H) 7.97 (s, 1 H) 8.13 (s, 1 H) 8.24 (d, J=8.36 Hz, 1 H). m/z (ESI) 450.1 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[CH2:38]Cl.Cl>C(OCC)(=O)C>[C:1]([O:9][C:10]1([CH2:38][C:37]2[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:35]([O:34][CH3:33])[CH:36]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reaction time: 8 h

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate (0.05 grams, 0.17 mmol, 0.5 M in toluene). While stirring at room temperature LiHMDS (0.3 mL, 0.3 mmol, 1.0 M, purchased from Fisher Scientific) was added. After approximately ten minutes a solution of 3,4,5 trimethoxybenzyl chloride (0.0553 grams, 0.26 mmol, purchased from Aldrich, 0.5 M in anhydrous DMF) was added. The reaction continued to stir overnight. The next day the reaction was acidified with 0.1M HCl, diluted with ethyl acetate and the two layers were separated. The aqueous layer was salted out and washed twice more with ethyl acetate. The combined organic solution was dried with sodium sulfate, filtered and concentrated. Purification was done on a Teledyne ISCO with silica gel using a hexanes/ethyl acetate gradient. This was followed by a subsequent reverse phase purification using Teledyne ISCO with a C18 column and a water with 0.1% formic acid, acetonitrile gradient. Yield (20%) 1H-NMR δ 8.05 (d, 2H), 7.57 (dd, 1H), 7.43 (m, 2H), 7.08 (d, 1H), 6.97 (s, 1H), 6.62 (d, 1H), 6.17 (s, 2H), 3.78 (s, 3H), 3.76 (m, 1H), 3.68 (s, 6H), 3.53 (m, 1H), 3.29 (d, 1H), 3.24 (d, 1H), 2.28 (s, 3H), 1.00 (t, 3H). Calculated mass for C28H29NO6, 475.20. Observed 498.2 (M+Na).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClC(Cl)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:23][CH:24]=1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To 6.2 g (46.5 mmol) of aluminum trichloride suspended in 50 ml of dichloroethane were added 3.02 g (30.2 retool) of succinic anhydride and 4.0 g (23.2 mmol) of 2-fluorobiphenyl were added thereto and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into hydrochloric acid containing ice, and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then recrystallized from chloroform to obtain 5.6 g (89% yield) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24][CH2:25][CH3:26])=[CH2:23])CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([O:24][C:22]([C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([C:22]([O:24][CH2:25][CH3:26])=[CH2:23])=[CH:8][CH:7]=3)[CH:3]=1)=[CH2:23])[CH3:26]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nc3cc(Br)ccc3nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nc3cc(C(=C)OCC)ccc3nc2c1
Yield: 88.1 %

Procedure:
To a solution of 2,7-dibromophenazine (13-2) (1.52 g, 4.50 mmol) in dry dioxane (75 mL) under N2 was added tributyl(1-ethoxyvinyl)stannane (3.34 ml, 9.89 mmol) and Pd(dppf)Cl2 (0.316 g, 0.450 mmol). The resultant mixture was heated at 100° C. for 4 h in a sealed tube. The crude reaction mixture was filtered through CELITE™545, and the volatiles were removed in vacuo. The crude brown solid was triturated with isohexanes and filtered to give 2,7-bis(1-ethoxyvinyl)phenazine as a brown solid (1.27 g, 88% yield). 1H NMR (CDCl3) δ 8.55-8.53 (2H, m), 8.19-8.15 (2H, m), 8.11-8.07 (2H, m), 4.98 (2H, d, J=3 Hz), 4.49 (2H, d, J=3 Hz), 4.03 (4H, q, J=7 Hz), 1.50 (6H, t, J=7 Hz) ppm. LC-MS (ESI): m/z 322.1 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[CH:20]=2)[N:15]=1>C1COCC1.CN(C=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:26][CH3:27])[N:15]=[C:14]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)[CH:23]=[N:22]2
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc(O[C@H]3CC[C@H](C(=O)O)CC3)nc2cc1OC

Procedure:
A mixture of cis/trans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmol) and NaH (60%, 160 mg, 4 mmol) in anhydrous THF/DMF(10 mL/2 mL) is refluxed for one hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (225 mg, 1 mmol). The resulting mixture is continued to refluxed for four hours. The reaction mixture is neutralized to pH 5 and extracted with ethyl acetate (2×50 mL). The combined organic solutions are dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (m.p. 90-93 ° C.). Anal. Calcd. for C17H20N2O5.0.5H2O: C, 59.89; H, 6.19; N, 8.22; Found: C, 59.91; H, 6.62; N, 7.90.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[O:10])=[C:4]([F:20])[CH:3]=1.[CH2:21]([O:23][C:24]1[C:25]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[N:26][C:25]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=4)=[C:24]([O:23][CH2:21][CH3:22])[CH:29]=3)=[CH:3][C:4]=2[F:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: O=C(Cc1ccc(Br)cc1F)Nc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(Cl)c(Cl)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (60 mg, 0.159 mmol), 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (61.3 mg, 0.159 mmol) and Cs2CO3 (156 mg, 0.477 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added PdCl2(dppf) (11.64 mg, 0.016 mmol) in one charge. The mixture was stirred at 130° C. in the microwave for 30 min. After LCMS analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated and evaporated to dryness to give crude product which was dissolved in DCM and washed with H2O and brine. Then the crude product was purified by preparative TLC (DCM/MeOH=40/1) to give pure product N-(3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (60.0 mg, 0.084 mmol, 52.7% yield): 1H NMR: (400 MHz, CD3OD) δ 7.95 (d, J=2.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.45 (s, 3H), 7.43-7.37 (m, 5H), 6.91 (d, J=8.6 Hz, 2H), 5.37 (s, 2H), 4.15 (m, 3H), 3.79 (s, 4H), 1.42 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 435 (M−120).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[N:14]([O:16][CH3:17])[CH3:15])=[CH:8][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Reactant: COc1ccc(CCBr)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCOc2ccc(NC(=O)N(C)OC)cc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 28.5 %

Procedure:
Into a solution of 8.8 g of sodium ethoxide in 200 ml of N,N-dimethylformamide is added 27 g of N'-(4-hydroxyphenyl)-N-methoxy-N-methylurea. To the mixture is added dropwise a solution of 27 g of 4-methoxyphenethyl bromide in 100 ml of N,N-dimethylformamide. The mixture is then gradually heated to 100° C., kept at the same temperature for 5 hours and then poured into ice water. The precipitated crystals are filtered, washed with water, ethanol and ether in this order and air-dried. The product is recrystallized from ethanol to obtain 11.8 g of N'-[4-(4-methoxyphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 100°-101° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([N:22]2[CH2:29][CH2:28][C:25]3([CH2:27][CH2:26]3)[C@H:24]([OH:30])[CH2:23]2)=[O:21])[C:13](=[O:31])[C@@H:12]1[CH3:32])=O)C1C=CC=CC=1.Cl>>[OH:30][C@@H:24]1[CH2:23][N:22]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([CH3:32])[C:13]2=[O:31])[CH2:29][CH2:28][C:25]21[CH2:27][CH2:26]2
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Yield: 98 %

Procedure:
In analogy to intermediate 12E, (S)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was hydrogenated without aqueous HCl to give the titled compound in 98% yield as light yellow oil. MS: 310.2 (MH+).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([NH2:4])[CH3:3].O=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[OH:15][C:13]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][CH:1]=[C:2]([CH3:3])[N:4]=1
Reactant: CC(N)CN
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1ncc(C)nc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of propane-1,2-diamine (5.7 mL, 66.4 mmol) in ethanol (100 mL) was added dropwise diethyl ketomalonate (10 mL, 65.6 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr, and then stirred for 1 day with heating under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethanol, and the solution was passed through silica gel (150 g, eluent, hexane:ethyl acetate=1:1→ethyl acetate). The eluate was concentrated under reduced pressure, and the precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (2.27 g, 19%) as a pale-orange powder. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (726 mg, 6.1%) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11](I)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.Cl[Pd]Cl>[Br:1][C:2]1[CH:12]=[C:11]([CH:14]=[CH2:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(I)cc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OCC)c(Br)c1
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCl2 (0.05 g, 0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through a celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm−1.