Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>[OH-].[Na+]>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]3[CH2:14][C:15]([OH:17])=[O:16])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
3-Methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester (6.0 g) was dissolved in TBF (60 ml) and 1N sodium hydroxide solution (60 ml) and stirred at room temperature for 6 hours. The solution was then cooled to 5° C. and adjusted to pH 9-10 by the addition of 10% hydrochloric acid. Nα(9-Fluorenylmethoxycarbonyl chloride (6.05 g) was then added portionwise, maintaining the pH at 9-10 by the addition of 1N NaOH solution. The reaction mixture was stirred at 5° C. for 16 hours. The solution was then adjusted to pH 1 by the addition of 10% hydrochloric acid. The solution was extracted with ethyl acetate (×2), dried (MgSO4) and evaporated. The title compound was obtained as a white foam (9.96 g), mass spectrum (API+) 411 [(M-C4H8)H+], C26H30N2O6 requires 466.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([N:20]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21]4=[O:27])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]1[CH:51]([NH2:53])[CH3:52])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:40][CH:39]1[CH:51]([NH:53][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([N:20]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21]4=[O:27])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH3:52])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(S(C)(=O)=O)n2)C1=O
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)n2)C1=O

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (EXAMPLE 29; 95 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine, diastereomer 1 (EXAMPLE 14 Step D; 100 mg) according to the procedure described in EXAMPLE 14, Step E. Mass spectrum (ESI) 670.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH:12]1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](Br)([Br:27])[Br:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]2[CH:13]([C:25]2([Br:27])[Br:26])[CH:12]1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC=CC1COC1CCCCO1
Reactant: BrC(Br)Br
Product: O=C(OCc1ccccc1)N1CCC2C(C1COC1CCCCO1)C2(Br)Br

Procedure:
Reaction of 1-benzyloxycarbonyl-2-tetrahydropyranyloxymethyl-1,2,5,6-tetrahydropyridine with bromoform under basic conditions, as in Section XXXVII, gives 3-benzyloxycarbonyl-7,7-dibromo-2-tetrahydropyranyloxymethyl-3-azabicyclo[4.1.0]heptane, which can be further converted into the desired compound by applying methods described in Section XXXVII.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:16].Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([O:16][C:18]([O:20][CH3:21])=[O:19])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[O:15][C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1c(OC)c(O)c2ccccc2c1O
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(OC)c(OC)c(OC(=O)OC)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene, prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran was added 1.40 g of methyl chloroformate followed by 1.50 g of triethylamine. The mixture was stirred at room temperature for 16 hours, filtered, then the solvent removed under reduced pressure. The residue was dissolved in diethyl ether, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the residue chromatographed on silica gel, eluting with a 1:1 mixture of methylene chloride and hexane, to give 2,3-dimethoxy-1,4-di(methoxycarbonyloxy)naphthalene, m.p. 53°-54° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Br:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: Sc1cccc(Br)c1
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2cccc(Br)c2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 3-bromothiophenol. Colorless oil (85%). MS (EI): 464.1 (M+H)+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)=[CH:5][C:4]=1[N+:22]([O-])=O.[H][H]>[Pd].C(O)C>[ClH:2].[ClH:1].[NH2:22][C:4]1[CH:5]=[C:6]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)[CH:7]=[CH:8][C:3]=1[Cl:2]
Reactant: O=C(CCC1C(=O)C2CCN1CC2)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(=O)CCC2C(=O)C3CCN2CC3)ccc1Cl

Procedure:
Hydrogenate 11.2 g (0.03 mole) of 2-[3-(4-chloro-3-nitrophenyl)-3-oxopropyl]-1-azabicyclo[2.2.2]octan-3-one hydrochloride over 1.5 g of 10% palladium on carbon catalyst in 250 ml of ethanol. Follow the progress of the reaction by hydrogen uptake and by thin-layer chromatography. When the reaction is complete remove the catalyst by filtration. To the filtrate add 5 ml of concentrated hydrochloric acid. Remove the solvent in vacuo to give the title compound.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[CH2:15]([NH2:18])[CH2:16][NH2:17].C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O1CCOCC1>[N+:10]([C:9]1[C:4]2[C:3](=[O:14])[NH:18][CH2:15][CH2:16][NH:17][C:5]=2[CH:6]=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reactant: NCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1NCCNc2cccc([N+](=O)[O-])c21
Yield: 25.9 %

Procedure:
2-fluoro-6-nitrobenzoic acid methyl ester (4.54 g, 22.8 mmol), ethylenediamine (1.50 mL, 22.4 mmol) and diisopropylethylamine (8.71 mL, 50 mmol) were dissolved in 1,4-dioxane (40 mL). The reaction mixture was then irradiated at 140° C. for 40 minutes. After cooling, the reaction mixture was poured over saturated ammonium chloride (50 mL), and organics were extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and reduced. The residue was then purified by flash column chromatography (0% MeOH/DCM-20% MeOH/DCM over 35 minutes) to afford 1.2 grams of 6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow oil. LC/MS (ESI)=208.24 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1)=O.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([CH3:35])=[N:32]2)=[CH:27][CH:26]=1>C(OC(=O)C)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([CH:35]=[CH:1][C:3]3[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=3)=[N:32]2)=[CH:27][CH:26]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A solution of aldehyde (Step 1) (5.2 g) and 7-chloroquinaldine were heated in 45 ml acetic anhydride for 48 hours. The reaction mixture was evaporated. Flash chromatography of the residue using 5% ethylacetate in hexane afforded the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH:11]([CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](O)=[O:13].Cl.[CH3:44][O:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[OH:10][CH:11]([C:12]([NH:46][O:45][CH3:44])=[O:13])[CH:15]([NH:23][C:24](=[O:42])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
DIPEA (200 μl, 0.567 mmol) was added to a suspension of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (250 mg, 0.544 mmol) and O-methylhydroxylamine hydrochloride (90 mg, 1.078 mmol) in dichloromethane (50 ml) at 5° C. After about 5 min 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (665 mg, 1.748 mmol) was added, the pH adjusted to 8 via addition of further DIPEA, and the mixture then stirred for 1 h at 5° C. and then overnight at room temperature. Then dichloromethane (50 ml) was added, washed 2× with 10 ml of water and brine, dried, filtered and concentrated to give 430 mg of the crude product which was purified by chromatography on silica gel (dichloromethane+11-12% methanol. Concentration of the combined fractions and drying afforded 224 mg of a white amorphous solid;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH2:18][CH:19]([OH:31])[CH:20]2[C:24](N3CCCC3)=[CH:23][C:22](=[O:30])[O:21]2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:17][CH2:18][CH:19]([OH:31])[CH:20]3[O:21][C:22](=[O:30])[CH:23]=[C:24]23)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCC(O)C1OC(=O)C=C1N1CCCC1)Cc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C2C(O1)C(O)CCN2Cc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
At room temperature, 176 mg (0.35 mmol) of tert-butyl [(6-chloropyridin-3-yl)methyl][3-hydroxy-3-(5-oxo-3-pyrrolidin-1-yl-2,5-dihydrofuran-2-yl)propyl]carbamate (cf. V-2) are stirred in a mixture of 7 ml of dichloromethane and 3.5 ml of trifluoroacetic acid for one hour. After concentration under reduced pressure, 10.5 ml of acetic acid are added to the residue, and the mixture is stirred at 100° C. for two hours. After concentration under reduced pressure, the residue is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (99:1 to 80:20). This gives (a) 6 mg (6% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-7-hydroxy-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one as a mixture of diastereomers and (b) 30 mg (32% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-5,6-dihydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1Cl>CS(C)=O>[CH:18]1([CH2:17][O:16][C:9]2[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6](=[O:21])[CH:5]=[C:4]3[NH:3][C:28]2[C:27]([Cl:30])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:22])[CH2:19][CH2:20]1
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OCC1CC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Temperature: 32 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Sodium hydride (60%, 14 g, 350 mmol) was added (caution: H2 gas evolution) to a solution of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (18 g, 69 mmol) and DMSO (200 mL) under N2. After 1 h at room temperature, 3,4,5-trichloropyridine (12.6 g, 69 mmol) was added portionwise with external cooling (internal temperature kept below 30° C.), and the reaction was warmed at 32° C. overnight. The reaction was quenched with water (40 mL) and adjusted to pH=6, with saturated potassium phosphate (KH2PO4). The resulting solids were collected by filtration, purified by silica gel chromatography (100:1; dichloromethane/methanol), and then triturated with ethyl acetate (300 mL) to give 22 g of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-quinolin-2(1H)-one as a straw yellow solid. MS (ESI): 406.1.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>O.[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: O
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
1.9 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 80 ml of water and the dispersion was stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered for removing the palladium black and the mother liquor was concentrated under a reduce pressure then the residue thus obtained was crystallized by adding a small amount of ethanol then crude crystals thus obtained were collected by filtration and recrystallized from ethanol to obtain 1.4 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril in colorless plate-like crystals. Melting point: 155.5°-156° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][S:22]([O:8][C@H:9]1[C@H:10]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:11][O:12][CH2:13]1)(=[O:24])=[O:23]
Reactant: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Triethylamine (1.99 mL, 14.3 mmol) was added to a cooled (0° C.) solution of trans-N-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide (1.99 g, 9.52 mmol) in dichloromethane (20 mL). Methanesulfonyl chloride (0.885 mL, 11.4 mmol) was then added and the reaction was stirred at 0° C. for 50 minutes. Saturated aqueous sodium bicarbonate solution (10 mL) was added, and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 10% to 50% ethyl acetate in heptane) to provide trans-4-[(isopropylsulfonyl)amino]tetrahydrofuran-3-yl methanesulfonate. Yield: 2.27 g, 7.90 mmol, 83%. 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.14 (s, 3H), 3.25 (septet, J=6.8 Hz, 1H), 3.77 (dd, J=9.5, 2.4 Hz, 1H), 3.96 (dd, J=11.3, 2.2 Hz, 1H), 4.08-4.16 (m, 2H), 4.21 (dd, J=11.3, 5.1 Hz, 1H), 4.77 (d, J=8.0 Hz, 1H), 5.15 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 16.48, 16.54, 38.28, 54.28, 59.49, 71.83, 71.87, 83.97.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:25][NH2:26])[CH:16]=1>>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:25][NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:16]=1
Reactant: NCc1cnc2ccccc2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3ccccc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and quinolin-3-ylmethanamine.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH2:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5]>CO.O.[Pd]>[NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH2:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5]
Reactant: NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
8.19 g of Z-β-Ala-His-NH2 are hydrogenated at room temperature under normal pressure for 15 hours in 200 ml of methanol/water (95:5) with 0.82 g of palladium-on-carbon (5% Pd). After filtering off the catalyst, evaporating off the solvent and drying, H-β-Ala-His-NH2 is obtained in the form of a colourless powder; Rf (L)=0.01.
Reaction SMILES: C(O[CH:5]1[O:14][C@@H:13]([CH3:15])[C@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[F:23])(=O)C.[BrH:24]>C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@H:13]([CH3:15])[O:14][C@@H:5]([Br:24])[C@@H:6]1[F:23])(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC1O[C@@H](C)[C@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](F)[C@H](Br)O[C@@H](C)[C@@H]1NC(=O)C(F)(F)F

Procedure:
Compound (8) (ie., the mixture of said α- and β-anomers above) is brominated in a conventional manner in solution of hydrogen bromide in acetic acid, to give 3-O-acetyl-2,4,6-trideoxy-2-fluoro-4-(trifluoroacetylamino)-α-L-mannopyranosyl bromide [Compound (9)] of the following formula ##STR16## as a 1-bromo-sugar. By the way, the corresponding 1-iodo-sugar can be obtained by reacting Compound (8) with iodo-trimethylsilane in anhydrous toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(c1ccccc1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and N-benzoyl-4-piperidone (87 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCN to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}phenylmethanone (152 mg, 84%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.19 min, m/z 423.35 (36), 421.34 (M++H, 100). HPLC tr=4.04 min (98.05%) 1H NMR (270 MHz, CDCl3) δ 1.24-1.44 (3H, m, CH2+NH), 1.76 (1H, m, ½CH2), 1.91 (1H, m, ½CH2), 2.72 (1H, hept, CHNH), 2.96 (1H, m, ½CH2), 3.80 (2H, m, CH2NH), 4.46 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.33-7.41 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 32.26, 33.09, 40.78, 45.67, 46.29 (CH2), 53.81 (CH), 118.95, 119.63, 124.57, 126.86, 127.97, 128.54, 128.75, 129.58, 129.85, 130.58, 131.78, 136.33, 154.35, 156.38 (ArC), and 170.00 (C═O).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:18]=[O:19])[CH:5]=1.[CH3:21][Zn]C.[Li+].[OH-]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:18]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:21])[C:3]([OH:2])=[O:20])=[O:19]
Reactant: C[Zn]C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C

Procedure:
Under nitrogen, Pd(dppf) (72 mg, 89 μmol) was added to a solution of 3-formyl-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (2.80 g, 8.97 mmol) in dioxane (40 mL). The mixture was stirred at rt and dimethyl zinc (11.2 g, 13.5 mmol, 12.1 mL of a 1.2M solution in toluene) was added. The mixture was stirred at 75° C. for 1 h. The mixture was cooled to rt before a 2M aq. LiOH solution (40 mL) was added. The mixture was stirred at rt for 2 h before it was concentrated. The residue was dissolved in EA and extracted with 1M aq. NaOH and water. The aq. extracts were acidified by adding 2N aq. HCl (30 mL) and then extracted with EA. The org. extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by prep. HPLC to give the title compound as a pale yellow powder (903 mg). LC-MS*: tR=0.27 min, [M−H]−=162.90; 1H NMR (D6-DMSO): δ 2.69 (s, 3H), 7.49 (d, J=7.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 10.29 (s, 1H), 13.20 (s, 1H).