Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[C@@H:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][CH2:9][C:10]2[NH:11][C:17](=[O:26])[C:18]3[C:19]([CH:25]=2)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C@@H:4]([CH2:12][OH:13])[CH2:3]1
Reactant: N#CCCCN1C[C@H](O)C[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCCN3C[C@H](O)C[C@@H]3CO)cc12

Procedure:
(3R,5R)-5-Hydroxymethylpyrrolidin-3-ol and 4-bromobutyronitrile are reacted in the presence of potassium carbonate in N,N-dimethylformamide to give 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile. In the same manner as in Example 1b (e) and using 4-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]butyronitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([NH2:12])=[S:11])=[CH:4][CH:3]=1.[CH:13](O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:12][C:10](=[S:11])[NH:9]2)=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: NC(=S)NNc1ccc(Cl)cc1
Product: S=c1ncn(-c2ccc(Cl)cc2)[nH]1

Procedure:
Twelve g of 1-(4-chlorophenyl)thiosemicarbazide was suspended in 60 ml of 95% formic acid, and the mixture was stirred under reflux for 24 hours. The mixture was then cooled, and the product precipitated. It was collected and washed with cold denatured ethanol, and was dried to obtain 6.1 g of the desired intermediate, m.p. 222°-224°.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27]>CN(C)C=O>[C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([O:18][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C1(O)CCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1([C@H](C)CS(=O)(=O)c2ccccc2)CCCC1
Temperature: 0 °C
Yield: 123.9 %

Procedure:
To a solution of 6a (2.40 g, 8.94 mmol) and imidazole (1.22 g, 17.9mmol) in N,N-dimethylformamide (20 mL) was added chlorotriethylsilane (2.2 mL, 13.1 mmol) in one portion. The mixture was stirred at ambient temperature for 3d. The mixture was poured into ice water, and extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 4.24 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 10%) to give 3.67 g (quantitative) of 7a, as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15]C)[CH:10]1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1>C(OCC)(=O)C.[H][H].[Pd]>[OH:15][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([O:8][CH3:1])[CH:10]1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC1CCCC(OCc2ccccc2)C1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCCC(O)C1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of racemic [1-benzyloxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51e, (3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL) and hydrogenated under 45 PSI of hydrogen with Pd—C 10% for 1 h. The reaction mixture was filtered over a nylon/fiberglass filter to provide, after concentration in vacuo 2.72 g of desired product 51f. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].[ClH:35].N1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:35].[Br:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[C:13]([O:25][CH3:26])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COc1cc2cc3c(Nc4cccc(Br)c4)ncnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a suspension of 0.1 g (0.267 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 3 mL of isopropanol is added 0.055 g (0.321 mmol) of 3-bromoaniline and 0.031 g (0.267 mmol) of pyridine hydrochloride. The mixture is brought to reflux for 15 minutes, then allowed to cool to room temperature. A yellow precipitate forms, which is filtered and washed with cold ethanol. Drying in vacuo provided 0.131 g of (3-bromophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine dihydrochloride as a yellow solid, mp 266-269° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[N:18]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of a mixture of 3-chlorosulfonyl-5-trifluoromethylbenzoic acid (0.5 g) and pyrrolidine (0.72 ml) in dichloromethane (5 ml) was stirred at room temperature overnight. After evaporation to dryness, water (50 ml) was added to the residue and adjusted to pH 1.0 by 1N hydrochloric acid. The resulting precipitates were collected by filtration, and dried under reduced pressure at 45° C. to give 3-(pyrrolidinosulfonyl)-5-(trifluoromethyl)benzoic acid (0.514 g) as a powder.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2].C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Yield: 65.9 %

Procedure:
Reflux dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (5.5 g) in toluene (200 cc) and cyclohexanone (70 cc) with aluminum isopropoxide (4.0 g) for 2.5 hours. Add water and anhydrous sodium sulfate, filter and isolate the crude product. Triturate with ice cold methanol to obtain dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17-one (3.6 g), m.p. 118°-125°, λmax. KBr 5.78 μ, 5.90 μ, 6.0 μ. An analytical sample recrystallized from methanol has m.p. 163°-166°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:2]([O:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)=[C:3]([CH:6]=2)[CH:4]=[O:5])[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CSc1ccc(O)cc1
Reactant: CC(C)N1CCN(Cc2ccc(F)c(C=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ccc(CN3CCN(C(C)C)CC3)cc2C=O)cc1
Temperature: 90 °C
Yield: 107.7 %

Procedure:
A mixture of 2-fluoro-5-(4-isopropyl-piperazin-1-ylmethyl)-benzaldehyde (513.7 mg, 1.943 mmol), 4-methylsulfanyl-phenol (326.8 mg, 2.138 mmol), and K2CO3 (845.2 mg, 5.829 mmol) in DMF (9.0 mL) was heated at 90° C. for 3 days. After cooling to rt, the mixture was diluted with Et2O, washed with 1 N NaOH and brine, dried (Na2SO4), and concentrated. Purification by FCC followed by reverse phase chromatography gave the desired product (804.5 mg, >100%). MS (ESI): mass calcd. for C22H28N2O2S, 384.19; m/z found, 385.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH:43]([NH:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1)=[O:44].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:48]4[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][CH:43]=[O:44])[CH:47]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: O=CNc1cccnc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(NC=O)c3)CS[C@H]12)c1nsc(N)n1
Reaction time: 1.33 h
Yield: 2.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-formylaminopyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)] (244 mg, 2 mmoles) in DMSO (2 ml) was stirred at room temperature for 1 hour, and poured into ethyl acetate (200 ml). The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness in vacuo. The residue was dissolved in water (40 ml), neutralized with NaHCO3 and then filtered to remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml), with water and 5% CH3OH, 10% CH3OH, 20% CH3OH and 30% CH3OH. The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (I-1F) (E) as a tan powder. Mp. >170° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.C(O)(=O)C.[Br:17]Br>O>[Br:17][C:3]1[C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=2[S:12][C:2]=1[CH3:1]
Reactant: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc2[nH]c(=O)[nH]c(=O)c2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A brown glass round-bottom flask was charged with 6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione (2.70 g, 14.8 mmol) and glacial acetic acid (30 ml). Bromine (2.70 ml) was added and the mixture stirred at ambient temperature for 4 hours. The resultant mixture was diluted with water (30 ml) and the solid was collected by filtration, washed thoroughly with water and then dried in vacuo to give 5-bromo-6-methyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a brown solid (2.43 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.I([O-])(=O)(=O)=[O:16].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[S:9](=[O:16])[CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)c1cc(Br)cc2c1NCCS2
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1NCCS2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-1,4-benzothiazine-5carboxylic acid (500 mg) in methanol (80 ml) was added 0.05 M sodium metaperiodate solution (40 ml). The mixture was stirred for 5 hours at room temperature, then diluted with water (500 ml) and concentrated until crystals began to separate. The crystals were collected and dried to give the title compound (300 mg, 57.5% which was recrystallized from ethanol to give pale yellow crystals, mp 254°-255° C. (decompd.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[C:4]([CH3:16])[N:3]=1.[CH:17]([C:20]1[CH:28]=[CH:27][C:26]2[NH:25][N:24]=[CH:23][C:22]=2[C:21]=1B(O)O)([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:17]([C:20]1[C:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[C:5]([CH:14]=[O:15])=[C:4]([CH3:16])[N:3]=2)=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc2[nH]ncc2c1B(O)O
Reactant: COc1ccc2c(Cl)nc(C)c(C=O)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(-c3c(C(C)C)ccc4[nH]ncc34)nc(C)c(C=O)c2c1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 1-chloro-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde (670 mg, 2.84 mmol), 5-isopropylindazole-4-boronic acid (580 mg, 2.84 mmol), Pd(PPh3)4 (164 mg, 0.14 mmol), and Na2CO3 (4.3 ml of 2M in H2O) in dioxane (15 ml) is heated for 18 h at 100° C. Usual work-up followed by flash chromatography over silica gel gives 342 mg of 1-(5-isopropyl-1H-indazol-4-yl)-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 8.68 (s, 1H), 7.65-7.37 (m, 3H), 7.42 (d, 1H), 7.01 (d, 1H), 4.01 (s, 3H), 3.15 (s, 3H), 2.71-2.63 (m, 1H), 1.22 (d, 3H), 1.10 (d, 3H).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[C:45](Cl)=[O:46]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:45]([C:36]3[CH:37]=[CH:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=3)=[O:46])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4ccccc4c3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 2-naphthoyl chloride as a colorless oil (93%). M+ (ESI): 594.4. HPLC, Rt: 5.96 min (Purity: 93.2%).
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:23])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[C:11]([OH:13])=[O:12].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]1[C:11](=[O:13])[O:12][C@H:9]1[CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 22.5 %

Procedure:
In a four necked round bottom flask, Et3N (3.75 mL, 26.9 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(pentyloxy)carbonyl]amino}butanoic acid (2 g, 8.96 mmol) in dry CH2Cl2 (100 mL) under argon. After cooling at 0° C., PyBOP (6.1 g, 11.6 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The solvent was removed under vacuum and crude purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.539 g) was further triturated with cyclohexane, yielding a pure compound (0.434 g, 22.5%) as white solid. MS (ESI) m/z: 214.21 [M−H]−. FTIR (cm−1): 3323, 3074, 2958, 2931, 2871, 1854, 1692, 1545, 1471, 1391, 1334, 1270, 1150, 1126, 1087, 1025, 982, 844, 823. 1H NMR (CDCl3): δ 0.91 (t, 3H); 1.31-1.35 (m, 4H); 1.47 (d, 3H); 1.60-1.67 (m, 2H); 4.06-4.14 (m, 2H); 4.84-4.91 (m, 1H); 5.42-5.49 (m, 2H).
Reaction SMILES: [N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8])=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
8 g (17.4 mmol) of Boc-Pro-Gly-Pro-OBzl were dissolved in 100 ml of methanol, 0.5 ml of CH3COOH and palladium black were added, while stirring on a magnetic stirrer, and hydrogen was passed through for 2 hours. The solution was filtered, evaporated, evaporated 3 times with benzene and 2 times with ethyl acetate. Then, it was precipitated with ether hexane from acetone, and the precipitate formed in the flask was dried in a desiccator over P2O5/KOH and paraffin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: Oc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(OC2CCCCO2)c(F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
260.2 g (2.0 mol) of 2,4-difluorophenol and 252.4 g (3.0 mol) of 3,4-dihydro-2H-pyran are introduced into a 750 ml sulfation flask and cooled to 0° C. One drop of polyphosphoric acid is carefully added to the solution, and the mixture is stirred for a further 16 hours at 0° to 5° C. (check using GC and TLC). The mixture is then rendered alkaline using a little powdered sodium hydroxide. The product is distilled at 119°-120° C. in vacuo (22 mbar). 377 g (88% of theory) of a clear, colourless liquid are obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[C:3]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 78.1 %

Procedure:
An aqueous solution of 5 M NaOH (17.5 mL, 87.5 mmol) was added to a stirring solution of 15a (20.1 g, 51.6 mmol) in 130 mL of THF and 52.5 mL of water at room temperature. After stirring for 2 days, 3.1 mL of 5 M NaOH (15.5 mmol) was added, and stirring was continued for another 2 days. The THF was removed under reduced pressure, then the aqueous residue was acidified with 1 M HCl to pH 5 and extracted with diethyl ether. The combined organic layers were washed with brine and dried over MgSO4. The diethyl ether was removed under reduced pressure, and the resulting crude powder was recrystalized in hexanes to yield 15.1 g (78%) of white powder 16a. Mp 114-116° C. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.22 (3H, m, o-Ar), 3.05 (2H, t, 3JH—H=6.4 Hz, HO—CH2), 2.33 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.56-1.68 (4H, m, 2CH2), 1.36-1.47 (2H, m, CH2). 13C-NMR (100 MHz, CDCl3, δH ppm): 180.26, 144.36, 128.62, 127.66, 126.79, 86.30, 63.24, 33.98, 29.63, 25.74, 24.48. HRMS (EI): m/z calcd 374.1882 (C25H26O3), found 374.1883 [M]+.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22].[H-].[Na+]>C1COCC1>[CH3:25][O:24][C:20]([C:21]1[S:22][C:2]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=2[C:4]=1[CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=[O:23]
Reactant: COC(=O)CS
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2cc(F)ccc2c1C1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 33.6 g (0.126 mol) of 1-[4-(2,4-difluoro-benzoyl)-piperidin-1-yl]-ethanone and 13 mL (145 mol) of methyl thioglycolate in 320 mL dry THF was added 5.8 g (145 mol) of 60% sodium hydride in mineral oil in portions. The reaction mixture was heated to reflux overnight, allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was then partitioned between 300 mL of CH2Cl2 and 200 mL of water. The aqueous layer was further extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue which was then triturated with hexanes/EtOAc to give 27.5 g (65%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C17H18FNO3S, 335.1; m/z found, 336.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz, a mixture of amide rotamers): 7.12 (m, 2H), 6.92 (dt, J=8.41, 1.77 Hz, 1H), 4.43 (d, J=3.79 Hz, 1H), 4.43-4.36 (m, 1H), 3.82 (bt, J=14.65 Hz, 1H), 3.57 (s, 3H), 2.92-2.79 (m, 1H), 2.38-2.34 (m, 1H), 1.94 (s, 1.5H), 1.93 (s, 1.5H), 1.86-1.72 (m, 1H), 1.47-1.38 (m, 1H), 1.38-1.27 (m, 0.5H), 1.27-1.16 (m, 1H), 1.15-1.03 (m, 0.5H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[N:15]1[N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=2)[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: CNc1cccc(Br)n1
Product: CNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 14285.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-methyl-amine (105 mg, 0.56 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by C18 flash chromatography (water to water/acetonitrile 3:2) to yield 22 mg (80 mmol, 14%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine as a white solid (M.P.=150-154° C.).