Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1Cl
Temperature: 142.5 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
3.70 g of diethyl (3-chloro-2-pyridyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.95 g of sodium chloride and 0.49 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 135 to 150° C. The reaction mixture was allowed to cool to room temperature, then, water was added to the reaction mixture, and extracted with ethyl acetate. After liquid separation, the organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 2.57 g of ethyl (3-chloro-2-pyridyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=2)O1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:55].Cl>>[ClH:1].[ClH:55].[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:34]3[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[N:38][CH:39]=3)=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(C#N)nc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (77 g, 0.21 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (72 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (100 g, 95%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 9.46 (d, J=2.2 Hz, 1H), 9.21 (s, 1H), 8.70 (dd, J=8.2, 2.2 Hz, 1H), 8.63 (d, J=8.9 Hz, 1H), 8.47 (d, J=8.9 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 5.58-5.50 (m, 1H), 3.14 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.77 (s, 3H), 2.49-2.42 (m, 2H), 2.05-1.97 (m, 3H), 1.75-1.65 (m, 2H), 1.39-1.27 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC 96.2% (AUC), tR=8.88 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:15]4[CH2:18][C:17]([CH3:26])([NH:19]C(=O)C(F)(F)F)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:3][CH2:2]1>[OH-].[Na+].C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:15]4[CH2:16][C:17]([CH3:26])([NH2:19])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:28])[C:6]([C:29]([OH:31])=[O:30])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 55.7 %

Procedure:
A solution of 0.8 g (1.8 mmoles) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid (example 11) in a mixture of 10 ml of 1N sodium hydroxide and 2 ml of ethanol is refluxed for 3 hours. It is evaporated under vacuum and acetic acid is added. The product is filtered and washed with water and ethanol. 0.35 g (55%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3-amino-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid are obtained having a melting point of 298°-300° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[C:8]([N:10]=[C:11]1[NH:15][CH2:14][CH2:13][S:12]1)=[O:9].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][N:15]2[CH2:14][CH2:13][S:12][C:11]2=[N:10][C:8](=[O:9])[C:7]([F:6])([F:16])[F:17])=[CH:23][CH:24]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(N=C1NCCS1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 86.6 %

Procedure:
Dimethylformamide (2 mL) and tetrahydrofuran (18 mL) were added to 162 mg (0.82 mmol) of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide obtained by the above-described method, following which 198 mg of 2-chloro-5-chloromethylpyridine and 150 mg (1.09 mmol) of potassium carbonate were added, and the mixture was refluxed under heating for 20 hours. Following reaction completion, the reaction mixture was returned to room temperature, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified on a TLC plate (two 0.5 mm plates, developed with 100% ethyl acetate), giving 230 mg of the target compound (yield, 87%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:8]=[O:9]>>[CH2:8]([N:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[OH:9]
Reactant: C=O
Reactant: O=C1CNC(=O)N1
Product: O=C1CN(CO)C(=O)N1

Procedure:
reacting (i) the at least one hydantoin reactant and (ii) the at least one dehydrated formaldehyde source reactant or substantially anhydrous formaldehyde source reactant in the molten system, while removing reaction water, to yield anhydrous molten methylolhydantoin; and
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[CH2:14]([C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:22][CH:23]=1)[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:14]([C:18]1[CH:23]=[C:22]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([NH2:13])[CH:3]=2)[CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Reactant: CCCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: CCCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (1.00 g) prepared according to the same procedures as Preparation 2 in 1,2-dimethoxyethane (20 ml) were sequentially added 2-(3-butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.37 g), a 2M aqueous solution of sodium carbonate (10 ml), tricyclohexylphosphine (197 mg) and palladium acetate (79 mg) at room temperature, and the mixture was stirred at reflux for 3 hours. This reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and then the insoluble substance was filtered off through Celite. The filtrate was extracted with ethyl acetate, the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1 to 2/3) to give the titled compound (880 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25][I:26])[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[I:26][CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([O:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21][CH2:20]1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (20 g) in methylene chloride (400 ml) containing triethylamine (8.4 ml) was cooled to -5° and added dropwise with good stirring to a cooled (-5°) solution of methanesulphonyl chloride (3.77 ml) in methylene chloride (50 ml) at such a rate that the temperature did not exceed +1°. After 30 minutes a further portion of methanesulphonyl chloride (3 ml) and triethylamine (6 ml) was added in a small volume of methylene chloride. After 10 minutes the solution was washed with water, dried and evaporated to give a yellow solid (22.43 g). Crystallization of a small portion afforded an analytical sample of title compound, m.p. 142°-143°, [α]D +83.2°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])OC)=[N:6]1.C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:27])[NH2:17])=[N:6]1
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The solution of methyl (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from Example 33 A-5 is mixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride and stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction.
Reaction SMILES: COC(=O)CCCCCCCC=O.C(NCCC1C=CC=CC=1)C1C=CC=CC=1.C[O:31][C:32](=[O:57])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:50]([N:41]([CH2:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([OH:57])=[O:31])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COC(=O)CCCCCCCCN(CCc1ccccc1)Cc1ccccc1
Agent: COC(=O)CCCCCCCC=O
Agent: c1ccc(CCNCc2ccccc2)cc1
Product: O=C(O)CCCCCCCCN(CCc1ccccc1)Cc1ccccc1

Procedure:
The title compound, m/e=406.6 ([M+H]+), was produced in analogy with example 64, steps 1 to 4. Thus, 9-oxononanoic acid methyl ester was reacted in step 1 with N-benzyl-2-phenylethylamine, leading to 9-(benzyl-phenethyl-amino)-nonanoic acid methyl ester, which was hydrolyzed in step 2 to afford 9-(benzyl-phenethyl-amino)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-3-[9-(benzyl-phenethyl-amino)-nonanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[C:7]12([CH2:17][CH2:18]O)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>O>[C:7]12([CH2:17][CH2:18][Br:1])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: BrCCC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of hydrobromic acid (26.2 g, 48%), concentrated sulphuric acid (10.82 g), and 2-(adamantan-1-yl)ethanol (10.82 g, 0.06 mol) was stirred and heated under reflux for 6 h. After cooling, water (60 ml) was added to the reaction mixture and the mixture was shaken. The organic layer was separated, and was then extracted with ether (3×100 ml). The extracts were combined, washed with water (1×20 ml) and with sodium carbonate solution (20 ml, 10% w/v) and the ether solution was then dried (MgSO4). The ether solution was concentrated under reduced pressure to give a solid, which was recrystallised from aqueous ethanol, to afford 1-(adamantan-1-yl)-2-bromoethane as white plates, m.p. 71°-72°.
Reaction SMILES: S(=O)(=O)(O)O.B(O)(O)O.[Na+].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OCC(CO)O.[F:30][C:31]1[CH:32]=[C:33]([NH2:41])[C:34]2[O:39][CH2:38][CH2:37][O:36][C:35]=2[CH:40]=1>C(OCC)(=O)C.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[F:30][C:31]1[C:32]2[CH:19]=[CH:14][CH:15]=[N:41][C:33]=2[C:34]2[O:39][CH2:38][CH2:37][O:36][C:35]=2[CH:40]=1
Reactant: Nc1cc(F)cc2c1OCCO2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: OCC(O)CO
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc2c(c3ncccc13)OCCO2
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
Concentrated sulfuric acid (25 ml), boric acid (2.22 g, 35.6 mmol), iron (II) sulfate heptahydrate (831 mg, 2.99 mmol) and 3-nitrobenzene sulfonic acid sodium salt (7.25 g, 32.2 mmol) were stirred in a flask cooled with an ice-bath; glycerol (8.4 ml, 23 mmol) and 7-fluoro-2,3-dihydro-1,4-benzodioxin-5-amine (3.9 g, 23 mmol) were added followed by water (25 ml). The reaction was heated at 140° C. for 3 h, then cooled to rt. The mixture was poured onto ice-water (100 ml) and filtered. The filtrate was basified to pH 8 with 6N sodium hydroxide (130 ml) and then stirred with ethyl acetate (300 ml) for 0.5 h. The mixture was then filtered through celite and the phases separated. The aqueous layer was extracted with ethyl acetate (3×300 ml), the combined organics washed with brine, dried on magnesium sulphate, filtered and reduced to afford a crude which dissolved in ethyl acetate and purified by filtration over a silica pad to afford the compound as a pale green solid (2.78 g, 60%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[CH3:12])(=[O:10])=[O:9].Br[CH2:31][C:32]([OH:34])=[O:33].[H-].[Na+].Cl>O1CCCC1.O>[CH3:12][N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][O:1][CH2:31][C:32]([OH:34])=[O:33])(=[O:10])=[O:9]
Reactant: O=C(O)CBr
Reactant: COCn1c(-c2nccs2)cc2cccc(N(C)S(=O)(=O)c3ccsc3CO)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1COCC(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-3-sulfonamide (480 mg) and bromoacetic acid (178 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 95 mg), and the mixture was stirred at 80° C. for 12 hr. Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was stirred at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (98 mg, yield 22%) as pale-yellow crystals. melting point 189° C.
Reaction SMILES: [C:1]([N:11](C)[CH:12]([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)(OCC1C=CC=CC=1)=O.[ClH:23]>[Pd].C(O)C>[ClH:23].[ClH:23].[CH3:1][NH:11][CH:12]([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1
Reactant: CC(Cc1ccc(O)cn1)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC(C)Cc1ccc(O)cn1
Reaction time: 18 h

Procedure:
The mixture of 0.08 g of 2-(N-carbobenzyloxy-2-methylaminopropyl)-5-pyridinol, 5 ml of anhydrous ethanol saturated with anhydrous hydrogen chloride and 0.04 g of 10% palladium on charcoal is hydrogenated at room temperature and atmospheric pressure for 18 hours. It is filtered, the residue washed with ethanolic hydrogen chloride and the filtrate evaporated, to yield the 2-(2-methylaminopropyl)-5-pyridinol dihydrochloride, which is identical with that of Examples 15 and 16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 55 %

Procedure:
A solution of 20.0 g of 6-methoxy-1-indanone, 31.3 ml of 3-buten-2-ol, 53.5 ml of 2,2-dimethoxypropane and 200 mg of p-toluenesulfonic acid in 200 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux overnight. After cooling, the solution was washed with 50 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 50 ml of ethyl acetate, the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 13.6 g (55%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26].Cl.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[NH2:23][CH2:24][C:25]([N:27]([C:19]1[CH:20]=[CH:21][C:16]([N:14]2[CH:15]=[C:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[N:12]=[N:13]2)=[CH:17][CH:18]=1)[CH3:28])=[O:26]
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: CNC(=O)CN
Agent: [Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)CN)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.22 mmol), H-Gly-NHMe.HCl (110 mg, 0.88 mmol), CuI (42 mg, 0.22 mmol), N,N′-dimethylethylenediamine (24 μL, 0.22 mmol), cesium carbonate (440 mg, 1.4 mmol) in 5 mL dioxane in a sealed tube was stirred for 15 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C17H17ClN6O2S (M+H)+ 405.1, 407.1 (Cl pattern).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])C.[OH-].[K+]>C(O)C.O>[Cl:19][CH2:18][C:17]([NH:16][CH:5]([C:4]([OH:21])=[O:3])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])=[O:20]
Reactant: CCOC(=O)C(NC(=O)CCl)N(C(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CCl)NC(C(=O)O)N(C(=O)CCl)c1cscn1
Yield: 73 %

Procedure:
To a solution of 3.54 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine ethyl ester in 30 ml of ethanol is added dropwise a solution of 1.68 g of potassium hydroxide in 15 ml of water under ice-cooling, followed by the stirring for 15 minutes. Ethanol is distilled under reduced pressure and the residue is made acidic with 10% hydrochloric acid, followed by the extraction with ethyl acetate. The ethyl acetate layer is washed with water and dried. The distillation of ethyl acetate gives 2.38 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine as colorless crystals.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>O>[CH2:11]([OH:12])[C@@H:9]([C@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The galactose obtained from Example 2 above is redissolved in water and catalytic hydrogenation and crystallization are performed as under (c) above. D-galactitol is obtained in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of 4-amino-3-nitrophenol (1.0 g, 6.5 mmol) and TBSCl (1.32 g, 8.8 mmol) in DMF (10 mL) was added imidazole (0.88 g, 13.0 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (300 mL), and washed with brine (100 mL) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EtOAc 2:1) to obtain the title compound (1.85 g, 100%) as gray solid. 1HNMR (600 MHz, CDCl3) δ 7.54 (d, J=2.7 Hz, 1H), 6.96 (dd, J=8.9, 2.7 Hz, 1H), 6.70 (d, J=8.9 Hz, 1H), 0.96 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:23]([NH:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].S(=O)(=O)(O)[O-].[K+]>CO>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
42.3 Grams of methyl Boc-L-tyrosyl-D-alanylglycinate is dissolved in 200 ml of methanol and 200 ml of a 1 N solution of sodium hydroxide is added. The reaction mixture is allowed to stand for 30 minutes, then is adjusted to pH 3 with a 1 M solution of potassium bisulfate. The resulting precipitate is collected by filtration, washed with water and dried to give Boc-L-tyrosyl-D-alanylglycine.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:9][CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:9][CH2:10][Br:2]
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CCBr)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus tribromide (2.17 g) was added, dropwise, to a solution of 3,4-dichlorophenethyl alcohol (4.26 g) in carbon tetrachloride (30 ml). The mixture was stirred at room temperature for 10 minutes then heated under reflux for 2 hours. 5% Aqueous sodium carbonate (10 ml) was added dropwise and the mixture was extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica eluting with dichloromethane containing hexane (30% down to 0%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, yield, 1.8 g.