Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[N:32]1([C:38]2[N:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([S:44]([C:41]6[CH:42]=[N:43][C:38]([N:32]7[CH2:33][CH2:34][O:35][CH2:36][CH2:37]7)=[CH:39][CH:40]=6)(=[O:46])=[O:45])[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(N5CCOCC5)nc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (21 mg, 80 μmol) and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added and the resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method A to afford 18.7 mg of the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[BH4-].[Na+].[CH3:10][OH:11]>>[OH:4][CH:3]1[O:5][C@H:2]([CH2:10][OH:11])[C@@H:3]([OH:4])[C@H:10]([OH:11])[C@H:2]1[OH:5]
Reactant: CO
Reactant: O=C(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
The solution was diluted with MeOH (2.7 mL, total volume: 3.2 mL) and the pH value was adjusted to 1 by addition of trifluoroacetic acid. An aqueous solution of HAuCl4 (314 μL, 0.025M) was added. Then, 1N aqueous solution of NaBH4 (157 μL) was added in several portions with rapid shaking. The black suspension formed was shaken for an additional 2 h and the methanolic layer was separated by decantation[2]. The black solid was dissolved in water (700 μL) and purified by centrifugal filtering (AMICON MW 10000, 30 min, 14000 rpm). The process was repeated twice, until the nanoparticles were free of salts and starting materials. The residue in the AMICON filter was dissolved in 500 μL of water and lyophilised to afford 1.0 mg of BMIX I nanoparticles. TEM: average diameter 1.80 nm, 201 gold atoms, 71 chains, MW=63300.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](=[O:50])(=[O:49])[NH2:8])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-n-butoxy-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-n-butoxy-4-phenyl-5-sulfamylbenzoic acid is obtained crystallizing with 0.25 mole of water with a melting point of 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([CH2:18][OH:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C1COCC1.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:18][O:19][S:27]([CH3:30])(=[O:29])=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (28.5 g, 0.1 mol) and 15 g of triethylamine were introduced as initial charge in 150 ml of THF and the solution was cooled to 5° C. (11.4 g, 0.1 mol) of mesyl chloride were added at 0-5° C. within 20 min and the mixture was after-stirred at 0° C. for 2 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated by evaporation. The viscous residue (product weight 31 g) contained, according to LC/MS, 98% of the product.
Reaction SMILES: [OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C1(C#CC2(O)C=CC([CH2:42][CH2:43][C:44]3([CH3:52])[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]3)(O)C=C2)C=CC=CC=1>CN1C(=O)N(C)CCC1>[OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]([CH2:42][CH2:43][C:44]2([CH3:52])[O:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][O:49]2)[CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: CC1(C)COC(C)(CCC2(O)C=CC(O)(C#Cc3ccccc3)C=C2)OC1
Reactant: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC1(C)COC(C)(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OC1
Temperature: -78 °C

Procedure:
4-Hydroxy-4-(phenylethynyl)-2,5-cyclohexadiene-1-one (1.26 g, 0.006 mole), the compound of Example 1a and 25 mL of dry THF were placed in a dry 100 mL, three-necked round-bottomed flask under nitrogen. The reaction was cooled to -78° C. and treated dropwise with n-butyllithium (4 mL of 1.48M). The reaction was allowed to warm slowly to about 0° C. During this time, a white slurry formed. The reaction was cooled to -78° C. and treated with 4.6 mL of DMPU and one equivalent of the Grignard reagent prepared in Example 1b. The reaction was allowed to warm slowly to RT over a period of 1 hr, then quenched with ammonium chloride solution and extracted into ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated in vacuo. The residue was dried under vacuum overnight. The crude product was chromatographed using a flash silica gel column eluting with 1:4 EtOAc/hexane to yield a first compound-bearing fraction containing 1.5 g (68%) of the title 1,2-1,4 adduct and a third compound-bearing fraction containing 0.31 g (14%) of 1-(phenylethynyl)-4-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,5-cyclohexadiene-1,4-diol, the 1,2-1,2 adduct.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]([OH:10])(=[O:9])[C:5](C)(C)C.O.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([CH2:5][C:4]([O:10][CH2:12][CH3:13])=[O:9])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)=O
Yield: 188.2 %

Procedure:
Toluene (100 ml), ethanol (19.86 g, 431.16 mmol) and pivalic acid (31.64 g, 359.30 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (10.25 g, 53.90 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (9.09 g, 89.83 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl acetylacetate (13.2 g, 32%) was isolated in distillation.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:22])[CH:5]=1>O.C(O)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:22])[CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cc(F)c(N)cc1F
Temperature: 90 °C
Yield: 40.1 %

Procedure:
Sodium hydroxide (903 mg, 22.58 mmol) in water (7 ml) was added to a solution of diethyl (4-amino-2,5-difluorophenyl)propanedioate (4.32 g, 15.05 mmol) in ethanol (35 ml). The reaction mixture was heated to 90° C. under argon for 1 hr. The reaction mixture was allowed to cool and then the solvent was evaporated. The residue was acidified (2M HCl, 200 ml) and then extracted with ethyl acetate (200 ml). The organic layer was dried (Mg SO4) and the solvent evaporated. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0→25% ethyl acetate/hexane) to afford the title compound as a pale yellow oil (1.3 g). MS (ES+) m/z 216 [M+H+] (C10H11FNO2).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=O)[NH:7][C:8](=[O:14])[NH:9]2)([O-:3])=[O:2].[C:16]([O-:19])([O-])=O.[K+].[K+].[CH3:22]I>CN(C=O)C.O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:16](=[O:19])[N:7]([CH3:6])[C:8](=[O:14])[N:9]2[CH3:22])([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)c2c([N+](=O)[O-])cccc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c([N+](=O)[O-])cccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Step 1 intermediate (40 g, 193 mmol) in dry DMF (386 ml) was added anhydrous K2CO3 (133.51 g, 966 mmol) and the mixture was stirred at room temperature for 30 min. Methyl iodide (40 ml, 636 mmol) was added slowly with stirring and further stirred at room temperature for 24 h. The reaction mixture was diluted with water (1.5 lit) and the solid precipitated out was filtered, washed with water and dried to give 41 g of the product as yellow solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 7.89 (t, J=8.4, 1H); 7.67 (d, J=8.7, 1H); 7.54 (d, J=7.8, 1H); 3.54 (s, 3H); 3.24 (s, 3H). MS (m/z): 236.20 ([M+H]+).
Reaction SMILES: [CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3].Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:4]1[C:16]([O:17][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccc3ccccc3n2)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Reaction time: 48 h

Procedure:
The compound from Step 4 (400 mg) is dissolved in 3.0 ml of DMF and 400 mg of 2-(chloromethyl)quinoline hydrochloride is added, followed by 275 mg of K2CO3. The reaction is stirred for 48 hours, 3.0 ml of H2O is added and the product extracted into Et2O. After washing with brine, the organic phase is dried and evaporated to yield ethyl 5-allyl-6-(quinolin-2-ylmethoxy)-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[C@H:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:14]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Product: CCOC(=O)CCC(NC(=O)CCc1ccc(O)cc1)C(=O)OCC
Yield: 90.1 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and glutamic acid diethyl ester (1.34 g, 6.6 mmol) were used, 1.9 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]CC)=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[OH-].[Na+].Cl.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CCOC(=O)C1=CC(C)=CN2CCS(=O)(=O)N=C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of ethyl 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylate 2,2-dioxide (106 mg) in methanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1.05 mL) and water (1 mL), and the resulting precipitate was collected by filtration, washed successively with water and a small amount of THF, and dried to give the title compound (79 mg) as a pale-yellow solid.
Reaction SMILES: [H-].[Na+].O1CCCC1.[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:18]([Sn:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]I)[CH2:19][CH2:20][CH3:21]>C(OCC)(=O)C>[CH2:18]([Sn:22]([CH2:23][O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH3:21]
Reactant: OCCCN1CCOCC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)COCCCN1CCOCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 150 %

Procedure:
To a mixture of sodium hydride (60%, 278 mg, 6.96 mmol) and tetrahydrofuran (20 ml) was added N-(3-hydroxypropyl)morpholine (963 μl, 6.96 mmol) at room temperature. Then, the reaction mixture was stirred at 45° C. (external temperature) for 10 minutes. To the reaction mixture was added tributyl-iodomethyl-tin (2.0 g, 4.64 mmol) at 0° C. (external temperature). Then, the mixture was stirred at 45° C. for 1 hour. The reaction mixture was cooled at room temperature, diluted with ethyl acetate, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, heptane:ethyl acetate=9:1) to obtain the title compound (2.08 g, 6.96 mmol, 100%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1cc(NC(=O)C2CNCCO2)no1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)C2CN(C(=O)c3ccc(C(F)(F)F)cc3)CCO2)no1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a cold (0° C.) solution of morpholine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (75 mg; 0.259 mmol), 4-(trifluoromethyl)benzoic acid (49.2 mg; 0.259 mmol) and N,N-diisopropylethylamine (0.099 mL; 0.57 mmol) in anhydrous acetonitrile (2 mL) is added phosphorous oxychloride (0.023 mL; 0.259 mmol). The reaction mixture is left stirring at room temperature for 3.5 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/methylene chloride then trituation from hot methanol provides the title compound, m/z 426 [M+H+].
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[NH4+].[Cl-]>CCOCC.CCCCCC>[Cl:12][C:4]1[CH:3]=[C:2]([B:18]([OH:21])[OH:19])[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: Clc1cc(Br)c2c(c1)OCCO2
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)cc2c1OCCO2
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5-bromo-7-chloro-2,3-dihydro-benzo[1,4]dioxine (Preparation 22, 1.5 g, 6 mmol) in dry Et2O (45 ml) under nitrogen at −70° C. was added n-butyl lithium (2.63 ml of a 2.5M solution in hexane, 6.6 mmol) and the resultant mixture stirred for 1 hr. Trimethyl borate (0.92 ml, 8 mmol) was then added and the mixture stirred at room temperature overnight. Saturated aqueous NH4Cl was added (60 ml) and the aqueous layer extracted with Et2O (3×100 ml). The combined organic extracts were concentrated in vacuo. The residue was taken up in 1M aqueous NaOH and washed with Et2O (100 ml). The aqueous layer was then acidified with 2N aqueous HCl (pH 2) and extracted with diethylether (3×100 ml). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to afford the desired product as a white solid (1.12 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CN1CCOCC1.Cl[C:22]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[S:23]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[O:12][C:22]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[S:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: S=C(Cl)Sc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(Br)c(OC(=S)Sc2ccccc2)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Methyl 3,5-dibromo-4-hydroxybenzoate (1000 mg, 3.23 mmol) was dissolved in THF (16 mL) and N-methylmorpholine (0.709 mL, 6.45 mmol) was added. The mixture was cooled to 0° C. and phenyl chlorodithioformate (0.549 mL, 3.87 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc/hexanes) to yield the title compound as a clear oil (1491 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CCCCCCBr
Reactant: OCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCOCCCc1ccc(OCCCCCC#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL ) was added to a solution of DMF (35 mL) containing NaH (1.31 g, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to 80° C. After stirring for 1 h at 80° C., the reaction mixture was cooled to 0° C., and 6-bromohexanenitrile (5.78 g, 32.83 mmole) was added. The final mixture was re-heated to 80° C., and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na2SO4. and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). Rf=0.63 in 1/1 EtOAc/hexane. 1H-NMR (CDCl3, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN([C:32]([O:36][N:37]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.CON>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:37][O:36][CH3:32])=[O:28])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.10 mL, 1.5 mmol) and methoxyamine hydrochloride (0.12 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 1:2) to give (1R,10R,11S,16S)-5-hydroxy-N-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (95) (0.035 g, 16%) as a white solid. 1H NMR (CD3OD): δ 7.27 (d, 1H), 6.87 (d, 1H), 3.83 (s, 3H), 3.47 (m, 2H), 2.70 (m, 1H), 2.11 (d, 1H), 1.87-1.38 (m, 10H), 1.30-1.15 (m, 1H), 1.04-0.94 (m, 5H), 0.90 (s, 3H), 0.86 (s, 3H). MS m/z 434 (C23H33NO5S−H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[Br:14][C:15]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:16]=1[NH2:17]>ClC1C=CC=CC=1>[NH2:9][C:10]([NH2:11])=[NH:17].[ClH:13].[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:17][C:16]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=2[Br:14])=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: Nc1cc(Br)ccc1Br
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(N(C)C(=N)Nc2cc(Br)ccc2Br)c1
Product: N=C(N)N

Procedure:
A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol), 2,5-dibromoaniline hydrochloride (861 mg, 3 mmol), and chlorobenzene (2 mL) were combined in a dry round bottom flask equipped with water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine hydrochloride, as a white solid (780 mg, 59% yield).