Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[O:15])=[CH:10][CH:9]=1>C1COCC1.C1(C)C=CC=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=2)([OH:15])[CH:1]=[CH2:2])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)Oc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: C=C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Eb) 30.2 ml of 15% vinylmagnesium chloride solution in THF are added dropwise at 0° C. to a solution of 5.58 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 80 ml of toluene. The mixture is stirred at 0° C. for 2 h., then at room temperature for 2 h., subsequently hydrolyzed with 40 ml of ammonium chloride solution and extracted with methylene chloride. The extracts are dried, evaporated and purified over silica gel with toluene-acetone as the eluent. There are obtained 2.8 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-allyl]-phenol, MS: m/e 304 (M+H+, 1Br).
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])[S:4][CH3:5].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1>>[C:7]([NH:6][C:3](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[S:4][CH3:5])#[N:8]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1nccs1
Product: CSC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of dimethylcyanodithioimidocarbonate with 2-[(2-aminoethyl)thiomethyl]thiazole by the method described in Example 3(d) gave N-cyano-N'-[2-(2-thiazolylmethylthio)ethyl]-S-methylisothiourea. Fusion of this compound (2.15 g) with 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (2.02 g) on the steam bath for 6 hours, followed by chromatographic purification on a column of silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluant afforded the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[CH:16]([O:19][CH:20]([O:34][CH:35]([CH3:37])[CH3:36])[C:21]([CH3:33])([CH3:32])[C:22](=[O:31])[CH2:23][C@@H:24]([OH:30])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:18])[CH3:17].[Na+].[Cl-]>C(Cl)Cl>[CH:35]([O:34][CH:20]([O:19][CH:16]([CH3:18])[CH3:17])[C:21]([CH3:32])([CH3:33])[C:22](=[O:31])[CH2:23][C@@H:24]([O:30][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:37])[CH3:36]
Reactant: C=CC[C@H](C)[C@H](O)CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C(OC(C)C)OC(C)C)OC(=O)OCC(Cl)(Cl)Cl
Reaction time: 5 h

Procedure:
Trichloroethyl chloroformate (2.5 mL) and pyridine (2.95 mL) are added to a solution of (5R,6S)-1,1-diisopropoxy-5-hydroxy-2,2,6-trimethyl-8-nonen-3-one (2.9 g) in 40 mL of CH2Cl2 at 0° C., and the mixture is stirred for 5 hours before pouring into sat. aq. NaCl and extracting with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+]([O-])=O)[CH:4]=1)#[N:2].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.C(O)(=O)C>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]2[CH:7]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[S:14][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(C=O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(C#N)cc2s1
Temperature: 0 °C

Procedure:
4.08 g (23.2 mmol) of 4-cyano-2-nitrobenzaldehyde, 2.46 g (23.2 mmol) of methyl mercaptoacetate and 6.46 ml (46.4 mmol) of triethylamine are heated in 12.3 ml of DMSO at 80° C. for 2.5 h. The reaction solution is added to 400 ml of ice-water. The precipitate resulting after addition of 4 ml of acetic acid is filtered off with suction, washed twice with water and dried in vacuo at 50° C. overnight. 4.19 g (83.2% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2c(C(CC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate (0.039 g; 0.089 mmol) in methanol (2.7 mL) was added a 5% sodium hydroxide solution (2.68 mmol; 2.15 mL) and the reaction mixture was heated at 60° C. 18 h. An extra volume of 5% sodium hydroxide solution (1 mL) and ethanol (1 mL) were added and the reaction mixture was heated at 60° C. for 12 additional hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in water. The mixture was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. The white solid was crystallized in a mixture ethyl acetate-heptane to furnish 0.025 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].C(=O)([O-])O.[Na+]>C(O)CCC>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 2 h

Procedure:
—Sodium (8.98 g) was added in small portions in the course of 2 h to a refluxing solution of (3β)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-one (20 g) in dry n-butanol (587 ml). Heating was continued for another 2 h; then the reaction mixture was cooled and poured into a saturated aqueous solution of sodium hydrogen carbonate (1.5 l). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography of the crude product afforded (3β,20R)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (5.08 g) and (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (compound 3, 7.21 g).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1.Br[C:14]1C=CC(OC)=CN=1>>[CH3:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1
Reactant: COc1ccc(Br)nc1
Reactant: COc1ccc(CC(=O)O)nc1
Product: Cc1ccc(CC(=O)O)nc1

Procedure:
(5-Methylpyridin-2-yl)acetic acid was prepared using analogous procedures to those used for the preparation of (5-methoxypyridin-2-yl)acetic acid (SM-1ab) substituting 2-bromo-5-methylpyridine for 2-bromo-5-methoxypyridine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H]1([N:18]2[C:28]3[N:27]=[C:25]([NH2:26])[NH:24][C:22](=[O:23])[C:21]=3[N:20]=[CH:19]2)O[C@H](CO)[C@@H](O)[C@H]1O.[ClH:29].CO>CS(C)=O>[ClH:29].[CH2:1]([N:20]1[C:21]2[C:22](=[O:23])[NH:24][C:25]([NH2:26])=[N:27][C:28]=2[N:18]=[CH:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 ml (0.34 ml) of benzyl bromide were added dropwise to a suspension of 40 g (0.147 mol) of guanosine in 200 ml of dimethyl sulfoxide and the mixture was stirred at room temperature for 4 hours. It was treated with 100 ml of concentrated hydrochloric acid and stirred at room temperature for 30 minutes. It was then poured into 1200 ml of methanol, and the precipitate was filtered off with suction and washed with methanol.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:14][C@@H:15]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@:20]([CH3:41])([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:19][C@H:16]1OC)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:42]([OH:45])(=[O:44])[CH3:43]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[C:42]([O:45][C@@H:16]1[O:19][C@:20]([CH3:41])([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]1[O:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:44])[CH3:43]
Reactant: CO[C@@H]1O[C@](C)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1O[C@](C)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Concentrated sulfuric acid (97%, 99 mL) was added to a solution of 2,3,5-tri-O-benzoyl-1-O-methyl-4-C-methyl-β-D-ribofuranose (1.8 g, 3.6 mmoles) in a mixture of acetic acid (9.0 mL) and acetic anhydride (0.90 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h and diluted with ethyl acetate (50 mL) and brine (10 mL). The organic extract was washed with brine (3 times), with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was dissolved with a mixture of ethyl acetate and hexanes (1:4, v/v) and the b anomer of the title compound crystallized instantaneously. The white crystals were filtered to give 1.1 g (56%) of the title compound in its pure b anomer form. The filtrate was subjected to silica gel chromatography [ethyl acetate (20%) in hexanes] to give 0.6 g (32%) of the titled compound as an oil (3:1 mixture of a/b anomers).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:3]=[CH2:4].C(Cl)Cl.[OH:20][CH:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][CH2:10][C:11]([O:20][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:26][CH3:27])=[O:12])[CH:3]=[CH2:4]
Reactant: C=CCNc1cccc(CCC(=O)Cl)c1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNc1cccc(CCC(=O)OC(CC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 3-(allylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 3-(allylamino)hydrocinnamate as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:9][C:8]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1Cl
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1cc(C(=O)C=CN(C)C)ccc1Cl
Yield: 80.5 %

Procedure:
4.46 g (21.1 mmol) of N-(5-acetyl-2-chloro-phenyl)-acetamide were dissolved in 10.4 ml (9.34 g) (78.39 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 6.5 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was crystallized from ethyl acetate. 4.53 g of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-acetamide as a yellowish-white solid were obtained (yield 80.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]3)[CH:22]=[CH:23][C:24]=2[F:25])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CC1(c2ccc(F)c(N)c2)CC1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)CC1(c2ccc(F)c(NC(=O)[C@H](c3ccc(Cl)cc3)[C@@H](C)C(F)(F)F)c2)CC1

Procedure:
A solution of 70 mg (0.31 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 84 mg (0.31 mmol) of methyl [1-(3-amino-4-fluorophenyl)cyclopropyl]acetate, 179 mg (0.47 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 0.6 ml of pyridine in 2.4 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was separated directly, without further work-up, by preparative HPLC. This gave 106 mg (0.22 mmol, 72% of theory) of the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.41 mmol) and triethylamine (95 μL, 0.69 mmol) in methylene chloride (20 mL) was added dropwise 4-butoxybenzoyl chloride (103 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (75%) of the title compound as white crystals: mp 190-191° C.; [α]21D −49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 421 (0.6, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[S:24](Cl)(=[O:26])=[O:25])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:24]([C:16]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=3[N+:12]([O-:14])=[O:13])(=[O:25])=[O:26])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c([N+](=O)[O-])c1

Procedure:
Using General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (4.9 g, 32.6 mmol), 2,4-dinitro-benzenesulfonyl chloride (9.8 g, 36.8 mmol), pyridine (18 mL), methylene chloride (100 ml), 0° C.-rt, 0/N. Purification: precipitation from hot H2O. The title compound was recrystallized from ethyl acetate as a light-orange solid (9.5 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.0 (s, 1H), 9.27 (s, 1H), 8.88 (d, Hz, 1H), 8.58 (dd, J=2.2, 8.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.51 (d, Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), (dd, J=1.9, 8.3 Hz, 1H), 4.91 (s, 2H); MS (ESI) m/z=378 (M−1, negative).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH2:35][CH2:34][OH:33])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1CCC(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCC(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 104 mg (0.26 mmol) of 1-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 55 μl (0.26 mmol) of (tert-butyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off using a 4N HCl solution in dioxane. The purification is carried out by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(C)cc3)c2O1

Procedure:
The title compound was prepared (0.051 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.213 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cnccc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2C(F)(F)F)CC1

Procedure:
The reaction of 4-chloro-3-trifluoromethylpyridine (2.05 g, 9.4 mmol, Matrix Scientific) and tert-butyl 1-piperazinecarboxylate (2.1 g, 11.3 mmol, Aldrich) under the conditions of Example 3a afforded the crude product, which was purified by silica gel column chromatography (60% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 332 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]1C[C@@H:31]1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2.[CH:45](O)(C)C>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH:31]([OH:30])[CH2:33][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:36]=3[CH:37]=[CH:38][CH:39]=[N:40]4)[C@H:25]([CH3:45])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CC(C)O
Reactant: CN1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Product: C[C@@H]1CC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CCN1CC(O)COc1cccc2ncccc12
Temperature: 70 °C

Procedure:
Methylpiperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (57) (150 mg; 0.382 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (77.5 mg; 0.382 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→25% methanol in methylene chloride) affording the desired product (187.4 mg) as a solid foam. ESMS: MH+ 594.4 (base).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:49][CH3:50])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:48]=[C:27]([NH:26][C:7](=[O:9])[C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=5)[CH:28]=[CH:29][C:30]=4[O:49][CH3:50])=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(OC(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 50.3 %

Procedure:
Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:5]1[C:6]([O:8]C)=[O:7])[CH3:3].CO.[OH-].[Na+]>O>[CH3:3][CH:2]([N:4]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:5]1[C:6]([OH:8])=[O:7])[CH3:1]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
Methyl 1-(1-methylethyl)-5-oxo-prolinate (0.152 g, 0.82 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred for ˜4 hrs at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 1-(1-methylethyl)-5-oxo-proline (0.060 g) as a yellow oil which crystallized on standing.