Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CO.O>[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][S:13](=[O:2])[CH:12]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCCCC(O)CCN1C(=O)CSC1CCCCCCC(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Temperature: 0 °C

Procedure:
Sodium metaperiodate (0.75 g., 3.5 millimole) is added to a cold (0°-5° C.) solution of 7-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoic acid (1.24 g., 3.44 millimole) in methanol-water (5:4; v:v; 18 ml.). The resulting mixture is stirred and allowed to slowly warm to 25° C. (as the ice bath melts, etc.) over 16 hours. After removing the precipitated solid via filtration, the filtrate is diluted with cold water and extracted twice with chloroform. The organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo leaving an oily residue which is chromatographed on silica gel (20 g.). Elution with chloroform-acetic acid (25:1; v:v) provides the title compound as a viscous, essentially colorless oil.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=O.I[CH3:12].[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>CN(C=O)C>[CH3:2][C:3]1([CH3:12])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:14][C:13]1=[O:16]
Reactant: O=C1Cc2ccccc2O1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Oc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of benzofuran-2(3H)-one (20 g) dissolved in DMF (250 mL) was treated with iodomethane (33.4 mL) at 0° C. before adding potassium carbonate (134 g) portionwise over a period of 10 minutes under nitrogen. The resulting suspension was stirred at 25° C. for 3 days. The mixture was filtered and the solids washed with ethyl acetate. The filtrate was diluted with 2M hydrochloric acid, extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography eluting with 30% dichloromethane in iso-hexane). Pure fractions were evaporated to dryness to afford the subtitle compound (19.70 g). 1H NMR δ (CDCl3) 7.32-7.08 (m, 4H), 1.53 (s, 6H).
Reaction SMILES: P(OCC)(OCC)(OCC)=O.C([O-])(=O)C.[Na+].O.[Na+].[NH2:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH2:31][C:32]#[N:33])/[C:26]([O-:28])=[O:27])[N:24]=1>C(OCC)(=O)C.[Pd](Cl)Cl>[NH2:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH2:31][C:32]#[N:33])/[C:26]([OH:28])=[O:27])[N:24]=1
Reactant: N#CCO/N=C(\C(=O)[O-])c1csc(N)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOP(=O)(OCC)OCC
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
2.66 g (0.01 mol) of allyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic in 100 ml of ethyl acetate are treated while stirring with 17.73 mg (0.001 mol) of palladium chloride and 0.083 ml (0.0005 mol) of triethyl phosphate. After stirring for 10 minutes, 0.9 g (0.11 mol) of sodium acetate is added thereto. The reaction occurs after the addition of 1 ml of water and crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid sodium salt precipitates out. The mixture is stirred at room temperature for a further 24 hours, subsequently extracted twice with 30 ml of water each time, the aqueous solution is extracted once with ether and subsequently adjusted to pH 2 with 2N aqueous hydrochloric acid. After evaporation to dryness, the residue is dissolved in 50 ml of methanol, filtered and cooled. There are obtained 1.1 g (45.4%) of 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid of melting point 140°-142° C. (decomposition).
Reaction SMILES: N[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:3]([OH:5])[CH3:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14].C([N:22](CC)CC)C>C(O)C>[C:13]([N:17]([C@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)[CH:3]([OH:5])[CH3:4])[C:18](=[S:19])[NH2:22])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: CCN(CC)CC
Reactant: CC(O)[C@H](N)Cc1ccncc1
Solvent: CCO
Product: CC(O)[C@@H](Cc1ccncc1)N(C(N)=S)C(C)(C)C
Temperature: 50 °C

Procedure:
a solution of 1.41 g of (3R,2RS)-3-amino-4-(4-pyridinyl)-2-butanol in 30 cm3 of ethanol, to which are added 1.08 cm3 of tert-butyl isothiocyanate and then 2.16 cm3 of triethylamine, is heated for 16 hours with stirring at a temperature in the region of 50° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C., taken up in 10 cm3 of water, washed with twice 30 cm3 of dichloromethane, dried over magnesium sulphate, filtered, evaporated under the above conditions and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. 2 g of N′-tert-butyl-N′-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxypropyl]thiourea are obtained in the form of an orange-colored oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm). We observe a mixture of two diastereoisomers A and B in respective proportions of 70/30, δ=0.99 (d, J=6.5 Hz: 0.9H); 1.09 (d, J=6.5 Hz: 2.1H); 1.37 (s: 6.3H); 1.41 (s: 2.7H); 2.74 (dd, J=14.5 and 9 Hz: 0.7H); from 2.75 to 2.90 (mt: 0.6H); 2.93 (dd, J=14.5 and 5 Hz: 0.7H); from 3.55 to 3.80 (mt: 1H); from 4.35 to 4.60 (unresolved complex: 1H; 4.65 (unresolved complex: 0.3H); 4.88 (unresolved complex: 0.7H); from 7.10 to 7.25 (mt: 1H); 7.17 (broad s: 0.7H); 7.27 (broad d, J=6 Hz: 1.4H); 7.31 (broad d, J=6 Hz: 0.6H); 7.44 (broad s: 0.3H); from 8.35 to 8.50 (mt: 2H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:1](=[N:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCc1ccccc1)c1ccccc1
Product: NCc1ccccc1

Procedure:
Other specific hydrogenation processes which are within the scope of the instant invention, include the hydrogenation of (a) cyclohexene to obtain cyclohexane; (b) nitrobenzene to obtain aniline; (c) benzonitrile to obtain a mixture comprising benzylamine, toluene, and α-benzylideneaminotoluene; and (d) diphenylacetylene to obtain a mixture comprising cis-stilbene, trans-stilbene, and 1,2 diphenylethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:26]2[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cn1nccc1N
Product: Cn1nccc1NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-methylpyrazol-3-amine (9.7 mg, 0.12 mmol). The title compound was obtained as a solid (10.0 mg, 23% yield). MS m/z: 429.96, 431.96 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=1)[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O-:3])=[O:2].C=O.O.[BH3-][C:29]#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:29][N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][O:7][C:6]2[C:15]([C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine (316.5 mg) was dissolved in 2.7 mL acetonitrile, then added 37% formaldehyde/H2O (360 ul) and then NaBH3CN (90 mg). Upon addition of NaCNBH3 the reaction exothermed slightly. The reaction was stirred at RT and pH was maintained at ˜7 by addition of drops of glacial acetic acid. After about 1 h, the mixture was concentrated in vacuo, treated with 8 mL 2N KOH and extracted two times with 10 mL Et2O. The organic layers were washed with 0.5N KOH and then the combined organic layers were extracted two times with 1N HCl. The aqueous layer was basified with solid KOH and extracted two times with Et2O. This organic layer was then washed with brine/1N NaOH, dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give pure compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH2:14][Cl:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C1C=CC=CC=1>[ClH:15].[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:14][C:13]1[O:16][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CCl)o2)cc1
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCN(CC)Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Product: Cl
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 47 g (0.20 mole) of 5-(4-nitrophenyl)furfuryl chloride and 58 g (0.80 mole) of diethylamine in 250 ml of benzene was heated under reflux for 8 hrs. After cooling to room temperature, the solid diethylamine hydrochloride (28 g, 95%) was collected by filtration and discarded. The filtrate was washed with 10% aqueous Na2CO3 and water and dried over MgSO4. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in 250 ml of anhydrous ether and 50 ml of absolute methanol. The solution was treated with hydrogen chloride, and the solid which was deposited was collected by filtration to give 45 g (73%) of diethyl[5-(4-nitrophenyl)furfuryl]amine hydrochloride. Recrystallization from CH3NO2 gave an analytical sample, m.p. 220°-237° (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[S:6][C@@H:5]2[CH:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(C1C(=O)C(=[O:36])C=C(C(C)(C)C)C=1)(C)(C)C>O1CCCC1>[CH3:1][C:2]1([CH3:21])[S:6][C@@H:5]2[C:7]([C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:36]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2C(=O)C(=O)N2[C@H]1C(=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of 3.06 g. (10 mmol.) of 6-aminopenicillanic acid benzyl ester and 2.20 g. (10 mmol.) of 3,5-di-t-butyl-1,2-benzoquinone in 50 ml. of tetrahydrofuran containing 5 g. of 5A molecular sieves is maintained at 4° for 16 hours. The solution is decanted and treated with 3 g. of oxalic acid in 10 ml. of water. After standing at 4° for 6 hours most of the solvent is removed below ambient temperature and the residue is partitioned between benzene and water. The aqueous phase is extracted with additional benzene and the combined organic phases are dried (MgSO4) and evaporated to dryness to give a residue which is chromatographed on silica gel with benzene-ethyl acetate as eluant to give the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2C=N[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1(C)C=CC=CC=1>CCOCC>[I-:18].[CH:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N+:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:30]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: c1ccc(Nc2cnc3ccccc3c2)cc1
Reactant: ICCCCCc1ccccc1
Reactant: Cc1ccccc1
Solvent: CCOCC
Product: [I-]
Product: c1ccc(-c2cc3ccccc3[n+](CCCCCC3CCCCC3)c2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of phenylquinolin-3-yl-amine (100 mg, 0.46 mmol) in toluene (2 ml) and 5-iodopentylbenzene (373 mg, 1.36 mmol) in sealed pressure tube was stirred at 110° C. for 24 hours. The reaction mixture was allowed to cool to room temperature, diluted with Et2O (15 ml), and the resulting precipitate was filtered and washed with Et2O (3×20 ml). The crude product was purified by column chromatography using MeOH/Et2O as eluent. The pure product was an orange solid (75 mg). Mp: 140-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30]I>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:30])[CH2:24][O:23][C:22]3=[O:28])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 71.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (739 mg) described in Preparation Example 163 and methyl iodide (259 mg), the title compound (544 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.O[CH2:20]C1C=C2C(=CC=1)C=C(C(C)C(O)=O)C=C2.[H-].[Na+].CI.Cl>C1C=CC=CC=1>[CH3:20][O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reactant: COC(=O)C(C)c1ccc2cc(CO)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Product: COCc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 2 h

Procedure:
To a mixture of 24.4 g. of methyl 6-hydroxymethyl-2-naphthyl-α-methylacetate (prepared from 6-hydroxymethyl-2-naphthyl-α-methylacetic acid by esterifying the latter by means of the procedure described in Part A of this example) and 500 ml. of benzene are added 2.4 g. of sodium hydride. The resulting mixture is stirred for 2 hours; then 12.2 g. of methyliodide are added. The resulting mixture is next neutralized by the addition of aqueous 1N hydrochloric acid after it has been allowed to stand for 1 hour; the mixture is then washed with water, dried over sodium sulfate, and evaporated to give methyl 6-methoxymethyl-2-naphthyl-α-methylacetate.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2C=CC=CC=2)=[O:7])=[CH:4][CH:3]=1.BrN1[C:21](=[O:22])[CH2:20]CC1=O>C(Cl)(Cl)(Cl)Cl>[C:21]([O:7][CH2:6][CH3:8])(=[O:22])[CH3:20].[CH3:14][CH2:15][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 129 %

Procedure:
1 To a solution of 4-methylbenzophenone (3.0 g, 15.3 mmol) in 60 ml CCl4 was added N-bromosuccinimide (3.0 g, 1.1 eq) and AlBN (30 mg). The solution was refluxed for 4.5 h, then cooled to room temperature. The succinimide were removed by filtration, and the filtrate was concentrated to dryness. Recrystallization required large amounts of solvent and chromatography appeared a better alternative. The residue was chromatographed on silica gel eluting with 5% Ethyl Acetate/Hexane (3.44 g; 82% yield).
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14].CO.ClCCl>C(O)C>[F:14][C:13]([F:16])([F:15])[C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[S:9][CH:11]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NC(=S)N1CCNCC1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: FC(F)(F)c1csc(N2CCNCC2)n1
Temperature: 70 °C
Yield: 41 %

Procedure:
To a solution of 6.89 mmol 1-piperazinecarbothioamide in 10 ml ethanol was added 8.26 mmol 3-bromo-1,1,1-trifluoroacetone and the mixture was heated at 70° C. for 2 h. The mixture was then concentrated in vacuo and the residue resuspended in dichloromethane. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Chromatography (SiO2, methanol/dichloromethane) afforded the title compound as a yellow crystalline solid (yield 41%). MS (m/e): 238.1 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CNC2CCN(C)CC2)cc1
Yield: 93 %

Procedure:
1-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20 ml of methanol and added to a 100 ml flask. 4-Methylbenzylamine (1.21 g, 10 mmol) in 10 ml of methanol was added. Acetic acid (˜1.5 ml) was added until pH˜5. NaCNBH3 (1.26 g, 20 mmol) was slowly added. After 20 hrs magnetic stirring methanol was partly removed on Rotavapor (40° C.). Dichloromethane, water and 2M NaOH were added until pH˜10. The phases were separated and aq. phase was extracted twice with dichloromethane. The combined organic phases were washed with brine and dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 2.06 g crude (93%) 47AKU-5. TLC (20% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=219.1 (UV/MS(%)=89/98).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([NH2:29])[S:28][C:24]=2[CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([NH:29][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])[S:28][C:24]=2[CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2nc3ccc(F)cc3s2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 6-fluoro-benzothiazol-2-ylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H17FN2O5S [M+H]+: 405.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1.C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1COc2cc(C=C[N+](=O)[O-])ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1COc2cc(CC[N+](=O)[O-])ccc2O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 6-(2-nitrovinyl)-2,3-dihydro-1,4-benzodioxine-2-carboxylic acid ethyl ester (3.7 mmol) in dioxane (10 mL) and ethanol (10 mL) was added dropwise a suspension of NaBH4 (140 mg) in dioxane (4 mL) and ethanol (4 mL) under cooling to −10° C. This solution was stirred at −5° C. for 1 hour and then acetic acid was added. It was concentrated under reduced pressure. To the residue were added water and a 1N aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. The oily phase was washed with saturated aqueous ammonia and brine in turn, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and the title compound (790 mg) was obtained from the effluent with hexane/ethyl acetate=30/10 (v/v).
Reaction SMILES: C1([C@H]2[C@H](C3C4C(=CC=CC=4)NC=3)C(=O)NC2=O)C2=C3C(=CC=C2)CCCN3C=1.[CH2:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[Br:41])[CH:34]=[CH:33]1)[CH:30]=[CH2:31].[C:42](Cl)([C:44](Cl)=[O:45])=[O:43].[CH3:48][O-:49].[Na+]>ClCCl>[CH3:48][O:49][C:44](=[O:45])[C:42]([C:34]1[C:35]2[C:40](=[C:39]([Br:41])[CH:38]=[CH:37][CH:36]=2)[N:32]([CH2:29][CH:30]=[CH2:31])[CH:33]=1)=[O:43]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCn1ccc2cccc(Br)c21
Reactant: C[O-]
Agent: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1cc(C(=O)C(=O)OC)c2cccc(Br)c21

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1-allyl-7-bromo-1H-indole with (COCl)2 (oxalyl chloride) and sodium methoxide in a polar aprotic solvent such as dichloromethane to yield (1-allyl-7-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester, which is subsequently reacted with 2-(1H-indol-3-yl)-acetamide and tBuOK (potassium tert-butoxide) in THF to yield 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione. Reduction of the 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione by Mg in refluxing methanol, as in Example 2 procedure C, yields 3-(1-allyl-7-bromo-H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which is treated with 9-BBN (9-borabicyclo[3.3.1]nonane) and Pd(PPh3)4(tetrakis(triphenylphosphine)palladium) to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14].[O:26]1[CH:30]=[CH:29][C:28]([CH2:31][S:32][CH2:33][CH2:34][NH2:35])=[N:27]1>>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([NH:35][CH2:34][CH2:33][S:32][CH2:31][C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)=[CH:18][CH:17]=1)[CH3:12]
Reactant: NCCSCc1ccon1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)N=C2NCCSCc2ccon2)o1

Procedure:
When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to the procedure described in Example 17, Step A, and the resultant product is treated with one equivalent of 2-[(3-isoxazolylmethylthio]ethylamine, the title compound is thereby produced.