Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2.I[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Reactant: ICCN1CCOCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCN2CCOCC2)c2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Temperature: 85 °C

Procedure:
A mixture of 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (100 mg, 0.24 mmol), 4-(2-iodo-ethyl)-morpholine (90 mg, 0.37 mmol), N,N-diisopropylethylamine (63 mg, 0.49 mmol) and silver triflate (75 mg (0.29 mmol) in 1,4-dioxane (5 ml) was heated at 85° C. under nitrogen for 16 hours. Purification of the mixture by silica gel chromatography, eluted with a gradient of MeOH in CHCl3 led to 3-{5-[(2,4-dimethoxy-benzyl)-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 31%).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12](COCC[Si](C)(C)C)[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(OC([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43](O)=[O:44])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][C:43]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:44]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CCNCC3)ccnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc2c(cn1)[nH]c1nccc(N3CCN(C(=O)C[C@@H]4CCCN4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(piperazin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.2 mmol), (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (50 mg, 0.4 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (70 mg, 0.4 mmol), and triethylamine (0.1 mL, 0.7 mmol) in methylene chloride (2.5 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-70% ethyl acetate in heptane) to afford the title compound as a white foam, which was used in the next step without any further purification (140 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](=O)(OC(Cl)(Cl)Cl)[O:16]C(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:41]=3)[CH:38]=2)=[C:30]([F:50])[CH:29]=1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O1CCCC1>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:48]=[CH:49][C:28]([NH:27][C:15]([N:10]5[CH2:11][CH2:12][CH2:13][N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[C:9]5=[O:14])=[O:16])=[CH:29][C:30]=4[F:50])=[CH:38][N:37]3[CH:39]=2)=[O:44])[CH2:47][CH2:46]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1NCCCN1c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)N4CCCN(c5ccc(F)cc5)C4=O)cc3F)ccc2n1)C1CC1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 49.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (360 mg, 1.8 mmol) in tetrahydrofuran (5 mL) was added bis(trichloromethyl) carbonate (330 mg, 1.1 mmol), and the mixture was stirred at 70° C. for 3.5 hr. The mixture was cooled to room temperature, a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (300 mg, 0.92 mmol) in tetrahydrofuran (8 mL) and N,N-diisopropylethylamine (360 mg, 2.8 mmol) were added to the mixture, and the mixture was stirred at room temperature for 30 min. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=40/60→90/10) to give the title compound (250 mg, 49%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([NH:32][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol), benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCI (31.2 mg, 0.16 mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography of the residue over silica gel, using 20% ethyl acetate/hexane, gave the title compound (16.1 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.14 (t, 1H), 7.57 (d, 1H), 7.38-7.51 (m, 4H), 7.16-7.36 (m, 7H), 6.96-7.06 (m, 2H), 6.15 (s, 1H), 4.37 (d, 2H), 3.70 (s, 3H); ES-MS m/z 399.1 (MH+), HPLC RT (min) 3.72.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1F)[C:5]([OH:7])=[O:6].[N:12]1(C(OC(C)(C)C)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cl
Product: O=C(O)c1ccc(N2CCNCC2)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
3-Chloro-4-fluorobenzoic acid (1 g) was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.3 g) and DIPEA (1.9 g) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH solution was added thereto, followed by washing with EtOAc. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane (10 ml), and 4 M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-piperazin-1-yl benzoic acid hydrochloride (142 mg).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
n-Dodecanoyl chloride (8.74 g; 40 mmoles) is added dropwise to a solution of p-aminobenzoic acid (5.5 g; 40 mmoles) dissolved in pyridine (100 ml). The mixture is stirred for 3 hours and poured into water (3 L). The precipitate which forms is filtered and dried in vacuo to give N-(n-dodecanoyl)-p-aminobenzoic acid (11.01 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12](=[O:27])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[OH:64][CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]([N:68]3[CH2:69][CH2:70][CH:65]([OH:64])[CH2:66][CH2:67]3)=[O:25])=[CH:16][CH:15]=2)=[O:27])[C:8]([O:28][CH3:29])=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCNCC1
Reactant: COc1c(NC(=O)Nc2ccc(C(=O)O)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(NC(=O)Nc2ccc(C(=O)N3CCC(O)CC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
85 mg (0.22 mmol) of 4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalene-1-carboxylic acid (Example 17) was dissolved in 1 mL of DMF. To this clear solution was added sequentially, 92 mg (0.294 mmol) of TBTU, and 82 microL (0.59 mmol) of triethylamine. The clear yellow solution was stirred for 5 min, then 33 mg (0.33 mmol) of 4-hydroxypiperidine was added. The reaction was stirred overnight, then concentrated in vacuo. The resulting amber oil was extracted with EtOAc and water, brine, and then dried over magnesium sulfate. Concentration in vacuo provided an amber oil which was purified on silica gel, eluting with with 33% EtOAc-hexane to provide 57 mg (54%) of the title compound as a pale white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.C(N(CC)CC)C.C1(N)CCCCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28](=[O:30])[NH:44][CH:48]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:47]3)=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)O)c3ccccc23)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Carboxy-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 5 (400 mg, 0.92 mmol) was dissolved in dichloromethane (5 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (350 mg, 1.84 mmol), 1-hydroxybenzotriazole (186 mg, 1.38 mmol), triethylamine (280 mg, 0.38 mL, 2.76 mmol) and cyclohexylamine (0.14 g, 0.16 mL, 1.38 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (30 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over Na2SO4. Filtration and concentration in vacuo afforded a foam that was purified via flash column chromatography (98:2 dichloromethane:methanol) to give the title compound. Wt.: 320 mg (68%). 1H NMR (300 MHz, CDCl3) δ 8.61 (m, 1H), 8.31 (m, 1H), 8.26 (d, 1H), 7.68 (m, 2H), 7.59 (d, 1H), 5.91 (d, 1H), 4.64 (d, 1H), 4.12 (m, 1H), 3.82 (m, 2H), 3.22 (m, 1H), 2.68 (m, 2H), 2.13 (m, 2H), 1.79 (m, 2H), 1.57 (m, 6H), 1.38 (s, 9H), 1.27 (m, 4H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:21])[CH:18]=[N+]=[N-])=[CH:10][CH:9]=1)=[N-].[Cl-:23].[Na+].[ClH:25]>CO>[Cl:23][CH2:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:21])[CH2:18][Cl:25])=[CH:10][CH:9]=1
Reactant: Cl
Reactant: [Cl-]
Reactant: [N-]=[N+]=CC(=O)CCCc1ccc(CCCC(=O)C=[N+]=[N-])cc1
Agent: [Na+]
Solvent: CO
Product: O=C(CCl)CCCc1ccc(CCCC(=O)CCl)cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
About 42 millimoles of the 1,4-bis-(5'-diazo-4'-oxopentyl)-benzene obtained from the preceding reaction, dissolved in 190 ml of methanol, are slowly added dropwise to a mixture of 117 ml of 5 M sodium chloride solution and 117 ml of 2 N hydrochloric acid solution, with vigorous stirring. The mixture turns cloudy and gas is evolved. Stirring is continued for 30 minutes and the yellow crude product which has precipitated (18.3 g) is filtered off. It is chromatographed over a silica gel column (length 30 cm, diameter 7 cm), using chloroform as the mobile phase, and colorless crystals are obtained; these are recrystallized from isopropanol. 1,4-bis-(5'-Chloro-4'-oxopentyl)-benzene is obtained in 51% yield (6.7 g); melting point 70°-71° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[O:7][CH:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][CH2:25][CH2:26]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][CH2:25][CH2:26][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[C:3]([Si:2]([CH3:1])([CH3:13])[CH3:14])[O:7][CH:6]=1
Reactant: OCCCc1cc(F)c(F)cc1F
Reactant: C[Si](C)(C)c1cc(CCC(=O)O)co1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(CCC(=O)OCCCc2cc(F)c(F)cc2F)co1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-(5-trimethylsilyl-3-furyl)propionic acid (61.3 mg, 0.29 mmol), 3-(2,4,5-trifluorophenyl)propan-1-ol (55 mg, 0.29 mmol), 1,3-dicyclohexylcarbodiimide (66 mg, 0.32 mmol) and 4-dimethylaminopyridine (10 mg) in dichloromethane (3 ml) was stirred at room temperature overnight (17 hours). Most of the solvent was evaporated and the residue was purified by preparative TLC (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:27]1([NH:33][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncccc2C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]nicotinic acid (200 mg, 0.77 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (427 ul, 3.07 mmol) was added followed by cyclohexylamine hydrochloride (88 ug, 0.77 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (50 ml) and diethyl diethyl ether (50 ml). The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 35:65) as eluant to give a white solid which was recrystallised from diethyl diethyl ether/pentane to give N-cyclohexyl-2-[3-(methylsulfanyl)phenoxy]nicotinamide (134 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19]>O1CCCC1>[I:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccccc1O
Reactant: BrCc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1ccccc1I
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
Sodium hydride (60% oil dispersion) (7.8 g) was added portionwise to a ice-water cooled solution of o-cresol (21.1 g) in tetrahydrofuran (500 mL). The mixture was stirred 20 minutes and then 1-(bromomethyl)-2-iodobenzene (58 g) was added. The mixture was warmed to 60° C. for 16 h. Additional sodium hydride (2 g) was added and the reaction mixture heated for an additional 3 h. The reaction mixture was cooled and carefully quenched with water and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to an oil, which was triturated with cold hexane to provide a solid which was collected by filtration to yield 59.1 g (94%) of the title compound of Step B as a white solid, mp 106-108° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[C:8]=1[C@@H:9]1[CH2:27][C:26]([CH3:28])=[CH:25][CH2:24][C@H:10]1[C:11]([CH3:23])([CH3:22])[O:12]2)(=O)=O.C(Cl)Cl.[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][BH:37][O:36]1.C(N(CC)CC)C>ClC(Cl)C>[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][B:37]([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]3[C:8]=2[C@@H:9]2[CH2:27][C:26]([CH3:28])=[CH:25][CH2:24][C@H:10]2[C:11]([CH3:22])([CH3:23])[O:12]3)[O:36]1
Reactant: CCCCCc1cc2c(c(OS(=O)(=O)C(F)(F)F)c1)[C@@H]1CC(C)=CC[C@H]1C(C)(C)O2
Reactant: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCCCCc1cc2c(c(B3OC(C)(C)C(C)(C)O3)c1)[C@@H]1CC(C)=CC[C@H]1C(C)(C)O2
Temperature: 80 °C
Yield: 95.5 %

Procedure:
A solution of (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl trifluoromethanesulfonate (S30) (410 mg, 0.92 mmol, 1 equiv) in anhydrous dichloroethane (20 ml) was degassed with a steady stream on N2 for 20 min. To the solution was added PdCl2dppf.CH2Cl2 (113 mg, 0.19 mmol, 0.2 equiv), 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (400 μl, 2.76 mmol, 3 equiv) and triethylamine (770 μl, 5.52 mmol, 6 equiv). The mixture was heated to 80° C. under an atmosphere of N2 for 11 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/hexanes 4/6 (v/v) to afford 373 mg of the title compound as white semi solid (92% yield). Rf=0.32 (benzene/hexanes 1:1 (v/v)). 1H NMR (600 MHz, CDCl3, 20° C., δ): 7.09 (d, J=2 Hz, 1H) 6.71 (d, J=2 Hz, 1H) 5.44 (bd, J=4 Hz, 1H) 2.99 (dt, J=5 Hz, J=11 Hz, 1H) 2.60 (bdd, J=5 Hz, J=15 Hz, 1H) 2.49−2.52 (m, 2H) 2.10−2.17 (m, 1H) 1.83−1.90 (m, 2H) 1.74 (dt, J=5 Hz, J=12 Hz, 1H), 1.68 (s, 3H) 1.59 (p, J=8 Hz, 2H) 1.38 (s, 3H) 1.36 (s, 6H) 1.34 (s, 6H) 1.28−1.33 (m, 4H) 1.14 (s, 3H) 0.88 (t, J=7 Hz, 3H) 13C NMR (100 MHz, CDCl3, 22° C., δ): 152.9, 141.4, 134.5, 128.5, 128.1, 120.0, 119.9, 83.5, 76.1, 45.5, 40.4, 35.4, 33.5, 31.7, 30.9, 28.2, 27.5, 25.1, 24.6, 23.2, 22.6, 18.5, 14.0 (C-B not observed). 11B NMR (96 MHz, CDCl3, 22° C., δ): 29.9. Mass Spectrometry: HRMS-FIA (m/z): Calcd for [C27H41BO3+H], 425.32215. Found, 425.32224.
Reaction SMILES: ClCCCCO[C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-:30].[NH4+]>O1CCCC1>[Cl:30][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1([C:11]([C:10]2[CH:9]=[CH:8][CH:7]=[CH:20][CH:19]=2)([OH:12])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH2:18]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)(c1ccccc1)C1(OCCCCCl)C=CC=CC1
Reaction time: 2 h

Procedure:
Combine 4-(4-chlorobutoxy)benzophenone (8.1 kg, 13.47 mol) and tetrahydrofuran (60 L). Add a solution of benzylmagnesium chloride (21 L, 1.67M in tetrahydrofuran, 35 mol) over about 2.5 hours. After 2 hours, cautiously add aqueous saturated ammonium chloride solution (9 L) over about 1 hour and a precipitate forms. Filter the reaction mixture, rinse with tetrahydrofuran, and extract the filtrate with aqueous saturated sodium chloride solution. Evaporate the separated organic layer in vacuo to give 1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethanol.
Reaction SMILES: COC1C=CC(C[CH:8]2[S:15][CH:14]3[N:11]([C:12](=[O:25])[C@H:13]3/[N:16]=C\C3C=CC=CC=3O)[C:10]([C:26]([O-:28])=[O:27])=[C:9]2/[CH:29]=[C:30]2/[C:31](=[O:47])[N:32]([C@@H:35]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]3)[CH2:33][CH2:34]/2)=CC=1.O.CS([O:55][C:56](=O)/[C:57](/[C:69]1[N:73]=[C:72]([NH2:74])[S:71][N:70]=1)=[N:58]\[O:59]CC1C=CC(OC)=CC=1)(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:74][C:72]1[S:71][N:70]=[C:69](/[C:57](=[N:58]/[OH:59])/[C:56]([NH:16][C@@H:13]2[C:12](=[O:25])[N:11]3[C@@H:14]2[S:15][CH2:8][C:9](/[CH:29]=[C:30]2/[C:31](=[O:47])[N:32]([C@@H:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)[CH2:33][CH2:34]/2)=[C:10]3[C:26]([OH:28])=[O:27])=[O:55])[N:73]=1
Reactant: COc1ccc(CO/N=C(\C(=O)OS(C)(=O)=O)c2nsc(N)n2)cc1
Reactant: COc1ccc(CC2SC3[C@H](/N=C\c4ccccc4O)C(=O)N3C(C(=O)[O-])=C2/C=C2\CCN([C@@H]3CCN(C(=O)OC(C)(C)C)C3)C2=O)cc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (7R)-4-methoxybenzyl-3-((E)-((R)-1′-(tert-butoxycarbonyl)-2-oxo-[1,3′-bipyrrolidin]-3-ylidene)methyl)-7-((Z)-(2-hydroxybenzylidene)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((4-methoxybenzyl)oxy)imino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.