Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].O.CS([C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1)=O>C(O)(=O)C>[OH:1][C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Into a 8-dram vial, 19.10 M of Sodium hydroxide in Water (7.88 mL, 1.50E2 mmol) and Water (7.88 mL, 438 mmol) water were added. The mixture was heated at 100° C. N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (2.00 g, 5.49 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested no SM. The reaction was cooled to room temperature. Glacial acetic acid was added to adjust pH to 4. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and subsequently with Et2O. The resulting solid was dried under vacuum overnight to give N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (1.60 g, 92%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4].[ClH:24].Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:24].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[C:11]([C:21]([N:35]1[CH2:34][CH2:33][N:32]([CH2:31][C:30]3[CH:38]=[C:39]([O:43][CH3:44])[C:40]([O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:37][CH2:36]1)=[O:23])[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2ccc(C(=O)O)cc2cc1OCCCC
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1cc2ccc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OCCCC
Yield: 84.2 %

Procedure:
Using 6,7-dibutoxy-2-naphthoic acid (0.25 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.31 g), triethylamine (0.35 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.5 ml), an amidation as that described in Example 6 is carried out. The reaction mixture is purified by gel column chromatography (hexane:acetone=1:1) and converted to the hydrochloride in ethyl acetate to give 1-(6,7-dibutoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.4 g) as colorless prisms, m.p. 182°-185° C.
Reaction SMILES: C[C@@H](N)C1C=CC=CC=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:14][C@:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]
Reactant: CC1(Cc2ccc(Cl)c(Cl)c2)NC(=O)NC1=O
Agent: C[C@@H](N)c1ccccc1
Solvent: CC(C)=O
Product: C[C@@]1(Cc2ccc(Cl)c(Cl)c2)NC(=O)NC1=O

Procedure:
Advantageously, compared to this preparation which comprises six steps in all, the preferred process for the purposes of the invention, which is faster and more economical, enables (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)-1-propanol to be prepared in four synthesis steps from 3,4-dichlorophenylacetone. Essentially, the process consists in reacting the ketone by the Bucherer-Berg reaction with potassium cyanide and ammonium carbonate to obtain (+/-)-5-(3,4-dichlorobenzyl)-5-methylhydantoin, which is subjected in an alkaline aqueous-acetone medium to a stereospecific salification with (R)-(+)-α-methylbenzylamine so as to obtain the addition salt thereof with the (S)-(-) enantiomer of the hydantoin, which, being insoluble, is filtered off, and from which (S)-(-)-5-(3,4-dichlorobenzyl)-5-methylhydantoin is obtained in a state of optical purity greater than 98% by treatment in an acid solution.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[N:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2C)[C:51]([CH:54]([NH2:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[N:52][N:53]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:62][CH:54]([C:51]1[N:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:49]([CH3:48])=[N:53][N:52]=1)[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:38]
Reactant: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(Cc2ccccc2)NC(=O)Cc2c[nH]c3ccc(O)cc23)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide) to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.64-8.42 (m, 1H), 7.50-7.19 (m, 3H), 7.17-6.93 (m, 6H), 6.81 (dd, J=53.1, 21.8 Hz, 4H), 6.54 (d, J=8.8 Hz, 1H), 3.39-3.22 (m, 3H), 3.09-2.85 (m, 2H), 2.01 (d, J=15.7 Hz, 3H). MS (m/z) 452 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([NH2:29])=O)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]#[N:29])(=[O:12])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Yield: 36 %

Procedure:
A solution of compound 23 (100 mg, 0.24 mmol), pyridine (47 mg, 0.6 mmol) and (CF3CO)2O (76 mg, 0.36 mmol) in DCM (5 mL) was stirred at it for 2 hr. The reaction mixture was quenched with water and extracted with DCM. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the desired compound 24 (34 mg, 36% yield). LCMS (m/z): 394.2 (MH+).
Reaction SMILES: I[C:2]1[C:3]([O:25]C)=[CH:4][C:5]([O:23]C)=[C:6]([C:8]2[N:12]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=[CH2:28]>CCOCC>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH2:28][C:2]2[C:3]([OH:25])=[CH:4][C:5]([OH:23])=[C:6]([C:8]3[N:12]([C:13]4[CH:22]=[CH:21][C:16]5[O:17][CH2:18][CH2:19][O:20][C:15]=5[CH:14]=4)[N:11]=[CH:10][CH:9]=3)[CH:7]=2)=[CH:30][CH:31]=1
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccc3c(c2)OCCO3)cc1I
Reactant: C=Cc1ccc(C)cc1
Solvent: CCOCC
Product: Cc1ccc(CCc2cc(-c3ccnn3-c3ccc4c(c3)OCCO4)c(O)cc2O)cc1

Procedure:
12.6 Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole with 4-vinyltoluene, hydrogenation and ether cleavage gives the compound 5-{5-[2-(4-methylphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole.
Reaction SMILES: [N:1]1([C:8]2[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:30]1[C:34](B(O)O)=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1([C:8]2[C:9]([C:34]3[S:30][C:31]4[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=4[CH:33]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (2 mL) was added benzo[b]thiophen-2-ylboronic acid (180 mg, 1.00 mmol), K3PO4 (210 mg, 1.00 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (25 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylate as a light yellow solid (82 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCOCC3)c2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 35.2 %

Procedure:
0.211 g (0.0005 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 0.217 g (0.0025 mol) of morpholine and 1 ml of triethylamine. The mixture was stirred at 40° C for 72 hrs. and the solvent was then removed. The residue was partitioned in ethyl acetate and water and the organic phase was extracted with sat. sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 and there was obtained 0.07 g (35%) of 4(2-bromo-6-morpholine-4-ylpyridine-4-sulphonyl)-phenylamine as white crystals; m.p.: 244-245° C.
Reaction SMILES: C([O:3][C:4](=[O:29])/[C:5](=[N:25]/[O:26][CH2:27][CH3:28])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH2:27]([O:26]/[N:25]=[C:5](\[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)/[C:4]([OH:29])=[O:3])[CH3:28]
Reactant: CCO/N=C(/C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C

Procedure:
As in Example 306, a solution of (Z)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0. 141 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 30 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.07 g of (Z-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 114° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:21]([N:23]([CH2:24][CH2:25][O:26][CH3:27])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH3:22]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCNCCOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCOC)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-ethyl-2-methoxyethanamine (34322-82-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=370.6 [MH+].
Reaction SMILES: [CH:1]1([CH:5]=O)[CH2:4][CH2:3][CH2:2]1.[O:7]1[CH2:11][CH2:10][O:9][C:8]21[CH2:20][CH2:19][C@@H:18]1[C@@:13]34[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[C:26]=5[O:28][C@@H:12]23)[CH2:21][C@H:17]1[NH:16][CH2:15][CH2:14]4.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([CH2:5][N:16]2[CH2:15][CH2:14][C@@:13]34[C:27]5[C:22]6[CH2:21][C@@H:17]2[C@@H:18]3[CH2:19][CH2:20][C:8]2([C@@H:12]4[O:28][C:26]=5[C:25]([C:29]#[N:30])=[CH:24][CH:23]=6)[O:7][CH2:11][CH2:10][O:9]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=CC1CCC1
Reactant: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)NCC[C@@]351)OCCO4
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)N(CC2CCC2)CC[C@@]351)OCCO4
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of cyclobutane carboxaldehyde (19.45 g, 231.2 mmol) in dichloromethane (500 mL) was added (4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (25 g, 77.1 mmol). The reaction was stirred for 60 minutes at room temperature before sodium triacetoxyborohydride (32.7 g, 154.0 mmol) was added portionwise over 20 minutes. After one hour, the reaction was quenched with NaHCO3 solution and extracted with dichloromethane (×3). The dichloromethane phases were combined, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography eluted with dichloromethane to 7% methanol in dichloromethane to give (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (31.1 g, 98% pure LCMS, assume quant.); [M+H]+ 393.1.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].Br[CH2:52][CH2:53][OH:54]>O.[OH-].[Na+]>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:52][CH2:53][OH:54])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][OH:41])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 20 h
Yield: 47 %

Procedure:
N,N'-Bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(2,3-dihydroxypropylaminocarbonyl)-phenyl]urea (0.216 g, 0.157 mmol) was dissolved in a mixture of water (6 ml) and 2M aqueous NaOH (0.9 ml) together with 2-bromoethanol (0.067 ml). The mixture was stirred for 20 h, neutralized with a strongly acidic cation exchange resin and evaporated to dryness. Purification using preparative HPLC gave 105 mg (47%) of the product as a white solid.
Reaction SMILES: C(C[CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#N.[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[O:9][CH2:4][CH:5]1[CH2:15][C:14]([OH:17])=[O:16]
Reactant: N#CCC1COc2ccccc2O1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC1COc2ccccc2O1

Procedure:
A mixture of 175 g 2-cyanomethyl 1,4-benzodioxan, 250 ml water, 250 ml acetic acid and 100 ml concentrated sulphuric acid are heated to reflux for 48 hours. The reaction mixture is then poured in 5000 ml water and the whole is kept under stirring. The thus found crystalls are filtered, washed with water and dried, giving rise to 172 g (1,4-benzodioxan-2yl)acetic acid melting at 95°.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:9]=[C:10]2[CH2:31][C:15]3([CH2:30][C:17]4([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH2:16]3)[O:14][C:11]2=[CH:12][N:13]=1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].O1CCOCC1>CO>[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:8]2[CH:9]=[C:10]3[CH2:31][C:15]4([CH2:30][C:17]5([CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]5)[CH2:16]4)[O:14][C:11]3=[CH:12][N:13]=2)=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.30 mL) is added to a mixture of 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (0.10 g), 4-(methanesulfonyl)phenylboronic acid (0.08 g), 1,4-dioxane (1.5 mL), and methanol (0.5 mL) at room temperature. The mixture is sparged with Ar for 10 min prior to addition of PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (20 mg). The resulting mixture is heated to reflux temperature and stirred at this temperature for 2 h. After cooling to room temperature, water and methanol are added and the resulting mixture is filtered. The filtrate is concentrated and the residue is chromatographed on reversed phase (HPLC, methanol/water) to give the title compound. LC (method 2): tR=1.72 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCC1
Reactant: Fc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ncccc2F)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a 0° C. solution of 2-chloro-3-fluoropyridine (80.0 g, 611 mmol, 1.0 equiv) and cyclobutane carbonitrile (49.5 g, 611 mmol, 1.0 equiv) in toluene (500 mL) was added sodium hexamethyldisilazide (2.0 M in THF, 306 mL, 612 mmol, 1.0 equiv) in a dropwise manner. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 mL), and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2×300 mL), and the combined organic phases were washed with saturated brine solution (2×400 mL), dried over Na2SO4, concentrated to give a crude yellow oil, and chromatographed with silica gel (2-10% EtOAc/hex) to give 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (88 g, 83%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].C1COCC1.Cl>O.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CNc2cc(-c3ccc(OC)nc3)n[nH]2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(NCc3ccc(C(=O)O)cc3)[nH]n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A solution of 384 (672 mg, 1.99 mmol) and KOH (300 mg, 5.35 mmol) in 1:1:1 mixture of THF, MeOH and water (9 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH=4 by addition of 1M HCl and concentrated in vacuo. The residue was triturated with water and the solid was collected by filtration and dried to afford the title compound (640 mg, 99% yield). LRMS: (calc) 324.1; (found) 325.2 (M+H1)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][C:20](=[O:57])[CH:21]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].I[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74].Cl>O1CCCC1.CN(C)C=O.O>[CH2:3]([O:19][C:20](=[O:57])[C:21]([CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH3:59])([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C(CCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(=O)C(CCCCCCCCCCCCCCCC)(CCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Sodium hydride (72 mg, 3 mmol) was added in portions to a cooled (ice/water) solution of 2-hexadecylmalonic acid dihexadecyl ester (2.33 g, 3 mmol) in tetrahydrofuran (45 ml) under an argon atmosphere and the resulting mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated and the solid residue was redissolved in N,N-dimethylformamide (45 ml). A solution of 1-iodohexadecane (1.06 g, 3 mmol) in N,N-dimethylformamide (20 ml) was added and stirring was continued at room temperature for 24 hours. Water (75 ml) was added to the reaction mixture after the pH had been adjusted to about 5 with 2N HCl. The mixture was extracted with chloroform (3×75 ml) and the chloroform phase was washed with water (3×75 ml). The organic phase was dried with magnesium sulphate and the solvent was removed at reduced pressure. The residue was purified by flash chromatography (silicagel 60, chloroform/hexane). Yield: 66%. 1H-NMR (300 MHz, CDCl3): δ 0.88(t,12H), 1.26(m,108H), 1.60(m,4H), 1.85(m,4H), 4.09(t,4H). FAB-MS: 1024 (M+Na).