Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH:7](Cl)[C:6]=2[CH:17]=1.[Br:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH:7]([O:21][CH2:20][CH2:19][Br:18])[C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(c1)C(Cl)Cc1ccccc1S2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(OCCBr)Cc1ccccc1S2
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
8, 10-Dichloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 35.6 mmol, prepared as described in Coll. Czech. Chem. Commun. 33,183, 1968) was slowly added to a mixture of 2-bromoethanol (44 g, 0.352 mol) and powdered potassium carbonate (10 g, 0.072 mol) at 20° C. under stirring. After 6 h, dichloromethane (15 ml) was added and the reaction mixture was heated at 50° C. for 3 h. After cooling, dichloromethane (35 ml) was added and the mixture was filtered. Dichloromethane was evaporated and excess of 2-bromoethanol was distilled off in vacuo. The oily residue was dissolved in benzene (100 ml), washed with water (3×70 ml), dried (K2CO3) and the solvent evaporated to give 13.0 g of crude 8-chloro-10-(2-bromoethoxy)-10,11-dihydrodibenzo[b,f]thiepine as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:35][C:36](=[O:38])[CH3:37])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:35]/[C:36](=[O:38])[CH3:37])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10 mmole) of 1-triphenylphosphoranylidene-2-propanone. The mixture was stirred at room temperature under nitrogen for 5 hours, during which time some product precipitated from solution. The solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 3.0 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.6 δ (1H); doublet 7.5 δ (2H); doublet 7.4 δ (2H); doublet 6.95 δ (1H); doublet 6.6 δ (1H); multiplet 4.5 δ (1H); doublet of doublets 4.0 δ (1H); multiplet 4.2 δ (3H); singlet 2.45 δ (3H); singlet 2.4 δ (3H).
Reaction SMILES: BrCCCCCCCCO.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[O:27]([CH2:34][CH2:35][OH:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][CH2:35][O:36][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCOc1ccccc1
Reactant: BrCCCCCCCCOC1CCCCO1
Agent: OCCCCCCCCBr
Product: c1ccc(OCCOCCCCCCCCOC2CCCCO2)cc1

Procedure:
The title compound, m/e=407.6 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran, which was reacted in step 2 with 2-phenoxyethanol, affording 2-(8-(2-phenoxy-ethoxy)-octyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 8-(2-phenoxy-ethoxy)-octan-1-ol. This was oxidized in step 4 to 8-(2-phenoxy-ethoxy)-octanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-4-dimethylamino-3-[8-(2-phenoxy-ethoxy)-octanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 6.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.CC(O)(C)C.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>[C:17]1([CH3:16])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: CCCN(CCC)Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CCCN(CCC)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 47.4 %

Procedure:
N-[(6-Bromopyridin-2-yl)methyl]-N-propylpropan-1-amine (7.0 g, 26 mmol) was dissolved in 1,2-dimethoxyethane (100 mL). Tetrakis(triphenylphosphine)palladium(0) (1.49 g, 1.29 mmol) was added and the solution was heated to 50° C. for 15 minutes. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (4.44 g, 27.1 mmol) in 30 mL 1,2 dimethoxyethane was added followed by potassium tert-butoxide (5.79 g, 51.6 mmol) in 30 mL of tBuOH. The reaction was heated at 90° C. for 0.5 h. The solution was filtered through filter paper and concentrated. Flash chromatography gave 3.83 g of the title compound (48% yield).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>Cl>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:3]([OH:26])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2ncccc2F)cc1=O
Agent: Cl
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ncccc2F)cc1=O
Yield: 72.8 %

Procedure:
A mixture of 3-cyclopentyl-2-[4-(3-fluoro-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (3 g, 8.3 mmol) in a 6N aqueous hydrochloric acid solution (40 mL) was heated at reflux for 36 h. At this time, the resulting precipitate was collected by filtration and washed with water to afford 3-cyclopentyl-2-[4-(3-fluoro-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (2.1 g, 73%); LC-MS: tR=3.07 min, 348 [M+H]+. HPLC: tR=7.78 min, 97.01% at 214 nm, 97.79% at 254 nm. 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), δ 8.25 (s, 1H), 7.69-7.67 (m, 1H), 7.57-7.51 (m, 1H), 7.24 (s, 1H), 6.40-6.34 (m, 1H), 5.39 (dd, 1H, J=10.5 Hz, J=3.9 Hz), 2.27-2.17 (m, 1H), 2.05-1.97 (m, 1H), 1.71-1.44 (m, 7H), 1.19-1.07 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[NH:8][N:9]=1)[CH3:2].[CH3:33]I>>[CH2:1]([O:3][CH2:4][C:5]1[N:9]([CH3:33])[N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[CH:23][C:13]3=2)[CH:6]=1)[CH3:2]
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)[nH]n1
Reactant: CI
Agent: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n[nH]1
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with the compound from Example 117, 6-(5-ethoxymethyl-1H-pyrazol-3-yl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and methyl iodide.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21]C)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(/C=C/C=C/C(=O)NCc2ccccc2)ccc1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/C=C/c1ccc(O)c(O)c1)NCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-hydroxy-3-methoxyphenyl)-penta-2,4-dienoic acid benzylamide (118 mg, 0.38 mmol) [Example 5] in 50 mL of dichloromethane, 100 μl of boron tribromide (0.95 mmol) was added dropwise at −78° C. The mixture was stirred for 15 min at −78° C. and for 1 h at room temperature. Water (100 ML) was added, the organic layer was separated, dried with Na2SO4 and evaporated.
Reaction SMILES: [Li][C:2]([CH3:5])([CH3:4])[CH3:3].CCCCC.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1>C1COCC1>[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1(C)COC(c2ccccc2F)=N1
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2C(C)(C)C)=N1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A 1.7M solution of t-BuLi in pentane (161 mL, 274 mmol) was added dropwise to a solution of 2-(2-fluorophenyl)-4,4-dimethyl-2-oxazoline [cf. Meyers A. I. and Williams B. E., Tetrahedron Letters, 223-226(1978)] (48.0 g., 249 mmol) in THF (320 mL), maintaining the reaction temperature between -45 and -40° C. with a dry-ice/acetone cooling bath. The resulting reaction mixture was maintained at ≤-40° C. with a dry-ice/acetonitrile bath, and monitored to completion by GLC over 20 min. This mixture was poured onto ice and extracted three times with ether. These extracts were combined, dried (MgSO4), concentrated and distilled under vacuum to afford 56.87 g of 2-(2-tert-butylphenyl)-4,4-dimethyl-2-oxazoline, a 93% yield.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[CH:21][C:22]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:23][N:24]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: OB(O)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2ncc(-c3cccs3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and 2-thiopheneboronic acid as starting materials and by an operation similar to that of Example 162-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained solid was triturate and washed with hexane-ethyl acetate to give the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[NH:25][N:26]=[CH:27][N:28]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:32][C:33]#[N:34].O>CN(C=O)C>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[N:28]=[CH:27][N:26]([CH2:32][C:33]#[N:34])[N:25]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCl
Reactant: c1ccc(-c2cc3nnc(-c4ccccc4)n3nc2OCc2ncn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1cnc(COc2nn3c(-c4ccccc4)nnc3cc2-c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
The product from Example 72 Step c) (0.10 g) was suspended in DMF (5 ml). Sodium hydride (15 mg of a 60% dispersion in mineral oil) was added, and the mixture strrred at room temperature for 15 min. Chloroacetonitrile (41 μl) was added, and the mixture stirred as before for 2 days. Water (25 ml) was added, and the resultant precipitate filtered off and purified by flash chromatography (silica gel, 0 to 3% methanol in dichloromethane). The product was recrystallised from ethyl acetate/ethanol to yield colourless crystals (17 mg). 1H NMR (360 MHz, d6-DMSO) δ5.60 (2 H, s), 5.61 (2 H, s), 7.58 (6 H, m), 7.76 (2 H, m), 8.41 (1 H, s), 8.44 (2 H, m), 8.68 (1 H, s); MS (ES+) m/e 409 [MH+]. Anal. Found C, 64.62; H, 3.74; N, 26.82. C22H16N8O. 0.1 C4H8O2 requires C, 64.62; H, 4.06; N, 26.87%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([NH2:30])=[C:19]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:20]=3)[C:12]([CH:31]=O)=[N:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:33][NH2:34].[Na]>CO.ClCCl.ClCCl.CO>[NH2:30][C:18]1[N:17]=[CH:16][C:15]([C:13]2[C:12]([CH2:31][NH:34][CH3:33])=[N:11][N:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[CH:14]=2)=[CH:20][C:19]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CN
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CNCc1nn(C2CCN(C(C)=O)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Over a period of 5 minutes, a solution of 1-(1-acetylpiperidin-4-yl)-4-(6-amino-5-(1,3-benzoxazol-2-yl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (132 mg) in MeOH/dichloromethane (1:1) that had been cooled to 0° C., was added to a stirred solution of methylamine (0.153 ml, 0.31 mmol) dissolved in dichloromethane (6 ml) and methanol (6 ml). The resulting solution was stirred at 0° C. for 20 minutes. Sodium triacetoxyhydroborate (78 mg) was added at 0° C. to the mixture and stirred at 0° C. for 5 hours. The mixture was evaporated. A saturated solution of sodium bicarbonate was added and the mixture was extracted with methylene chloride, dried over magnesium sulphate, filtered and evaporated under reduced pression. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 micron silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness, tritured with hot acetonitrile, filtered and dried under reduce pressure to afford 1-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methylaminomethyl)pyrazol-1-yl]-1-piperidyl]ethanone (23 mg) as a solid. NMR Spectrum: (CDCl3) 1.86-2.11 (m, 2H), 2.15 (s, 3H), 2.13-2.24 (m, 1H), 2.24-2.33 (m, 1H), 2.60 (s, 3H), 2.73-2.84 (m, 1H), 3.21-3.32 (m, 1H), 3.96 (s, 2H), 3.97-4.06 (m, 1H), 4.31-4.42 (m, 1H), 4.70-4.85 (m, 1H), 6.97 (bs, 2H), 7.32-7.41 (m, 2H), 7.54 (s, 1H), 7.57 (dd, 1H), 7.73 (dd, 1H), 8.32 (s, 1H), 8.42 (s, 1H); Mass spectrum: M+H+ 446;
Reaction SMILES: [Cl-].Cl[C:3](=[O:8])[CH2:4][NH+:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=1/[CH:16]=[C:17]1\[C:18](=[O:28])[N:19]([CH2:26][OH:27])[C:20]2[C:25]\1=[CH:24][CH:23]=[CH:22][CH:21]=2>>[CH3:6][N:5]([CH2:4][C:3]([O:27][CH2:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:17](=[CH:16]/[C:11]2[NH:12][C:13]([CH3:15])=[CH:14][C:10]=2[CH3:9])/[C:18]1=[O:28])=[O:8])[CH3:7]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: C[NH+](C)CC(=O)Cl
Agent: [Cl-]
Product: Cc1cc(C)c(/C=C2\C(=O)N(COC(=O)CN(C)C)c3ccccc32)[nH]1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 2-chloro-N,N-dimethyl-2-oxoethanaminium chloride and (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2].Cl.[C:19](=O)([O-])[O-:20].[K+].[K+]>CO.C(Cl)(Cl)Cl>[CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:16])[O:20][CH3:19])[N:7]=1)[CH3:2]
Reactant: CCN=C(N)Nc1cnn(CCCCC#N)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN=C(N)Nc1cnn(CCCCC(=N)OC)n1
Reaction time: 60 h

Procedure:
A solution of 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile (1.35 g.) in MeOH (5 ml.) and chloroform (20 ml.) was saturated with gaseous HCl at 0° and the solution kept at 0° for 2.5 days. Evaporation of the solvent gave an oil which was basified with cold potassium carbonate solution and then extracted with chloroform to give methyl 5-[4-(2-ethylguanidino)1,2,3-triazol-2-yl]valerimidate (1.57 g.) which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:18]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=2[N:13](COCC[Si](C)(C)C)[CH:12]=1.B(Br)(Br)Br.N>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:18]([NH:20][C@H:21]([C:23]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27](=[O:35])[C:26]4=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]4[N:24]=3)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1
Reactant: COc1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(O)cc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 21.7 %

Procedure:
(S)-2-(1-((5-(2,4-Dimethoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (95 mg, 0.14 mmol) was treated with boron tribromide (1M in dichloromethane, 1.46 mL, 14.6 mmol) and a solution of ammonia (7N in methanol, 1.96 mL, 13.72 mmol) according to the method described in Example 41 to give 15 mg (21% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:31])=[C:6]([C:21]([I:30])=[C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:23]=1[I:24])[NH:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])([OH:3])=[O:2].[OH-].[Na+].Cl>O>[C:1]([C:4]1[C:5]([I:31])=[C:6]([C:21]([I:30])=[C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:23]=1[I:24])[NH:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([OH:3])=[O:2]
Reactant: COC(=O)CCCCCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(N(C)C(C)=O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCCCCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 136.5 g. of methyl 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)azelanilate and 180 ml. of water was treated with 10% aqueous sodium hydroxide (about 140 ml.), added dropwise until solution was complete. The mixture was heated on a steam bath for 10 minutes, 18 ml. more of 10% sodium hydroxide was added, and the mixture heated 1 hour longer. The reaction mixture was cooled, acidified with 3% hydrochloric acid, and the solid product collected, washed with water, dried and recrystallized from acetic acid to give 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)azelanilic acid as a colorless solid, m.p. 205°-208° C.
Reaction SMILES: [CH:1](/[CH:5]1[CH2:10][O:9][CH:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].[CH:18](=O)[CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH2:19]([C@H:18]1[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]2[O:7][CH2:6][C@H:5](/[CH:1]=[CH:2]/[CH2:3][CH3:4])[CH2:10][O:9]2)[CH2:16][O:17]1)[CH2:20][CH3:21]
Reactant: CC/C=C/C1COC(CCC(CO)CO)OC1
Reactant: CCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC/C=C/[C@H]1CO[C@H](CC[C@H]2CO[C@H](CCC)OC2)OC1
Temperature: 68 °C
Reaction time: 0.67 h

Procedure:
A solution of 1.50 g of (E)-2-[2-(5-but-1-enyl-1,3-dioxan-2-yl)ethyl]-1,3-propanediol and 2 ml of butyraldehyde in 40 ml of benzene was treated with 28.5 mg of p-toluenesulfonic acid monohydrate and stirred at 68° C. for 40 minutes. The reaction mixture was neutralized with a few drops of triethylamine and, after cooling, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product (2.15 g) was chromatographed on 40 g of silica gel with hexane/ethyl acetate 5% (v/v). 1.40 g of isomer mixture having a 52% trans/trans content were obtained. Two-fold recrystallization from hexane gave 0.41 g of pure (E)-trans-2-propyl-5-[2-(trans-5-but-1-enyl-1,3-dioxan-2-yl)ethyl]-1,3-dioxane, m.p. (C-SB) 42° C., cl.p. (SB -I) 117.8° C.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12](=[O:42])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([S:23]C(=O)C)[CH2:20][N:19]2[S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[O:17])[CH3:15])[CH3:11])=[CH:6][CH:5]=1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][C:30]([S:27]([N:19]2[CH2:20][C@H:21]([SH:23])[CH2:22][C@H:18]2[C:16]([N:14]([CH2:13][C:12]([N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][CH:6]=2)=[O:42])[CH3:15])=[O:17])(=[O:28])=[O:29])=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](SC(C)=O)CN2S(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CC(=O)N(C)c1ccc(C(=O)O)cc1)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To 106 mg (0.17 mmol) (2S,4R)-4-[[[[4-Acetylsulfanyl-1-(biphenyl-4-sulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester in 10 ml THF were added 10 ml 0.1 M LiOH at 0° C. and the solution was stirred at RT for 2 h, poured on 2 ml 1M KHSO4 and extracted with EtOAc. The combined organic layers were washed with brine and were dried with Na2SO4. The residue was titrurated with hexane to give 67 mg (69%) (2S,4R)-4-[[[[1-(Biphenyl-4-sulfonyl)-4-mercapto-pyrrolidine-2-carbonyl]-methyl-amino]-acetyl]-methyl-amino]-benzoic acid as white solid, MS: 568 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)[CH:2]=[CH2:3].Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:18][OH:19])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)CC(=O)c1cccnc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC=C)CC(=NO)c1cccnc1
Temperature: 70 °C
Yield: 77.8 %

Procedure:
2-(Diallylamino)-1-(3-pyridyl)ethanone (4.75 g, 21.96 mmol) is dissolved in ethanol (47 mL) under a nitrogen atmosphere. Hydroxylamine hydrochloride (3.55 g, 50.51 mmol) and pyridine (2.5 mL, 30.75 mmol) are then added. The resulting solution is heated at 70° C. under nitrogen for 140 minutes. The reaction is then cooled to room temperature and the solvent is partially evaporated under reduced pressure. The resulting residue is partitioned between 1 M aqueous sodium hydroxide (50 ml) and dichloromethane (250 mL). The phases are separated and the aqueous phase is re-extracted with ethyl acetate (250 mL). The organic layers are combined and the solvents are evaporated. The crude material is purified by silica gel column chromatography using a 0-10% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (3.95 g, 78%) as a mixture of E/Z isomers. ES/MS (m/e): 232 (M+1).