Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4]=1[CH2:10][CH3:11])[CH3:2].[CH2:12]([N:30]1[C:35]([CH3:37])([CH3:36])CC(O)[CH2:32][C:31]1([CH3:40])[CH3:39])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:12]([N:30]1[C:31]([CH3:32])([CH3:40])[CH2:39][CH:1]([C:3]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4]=2[CH:10]2[CH2:40][C:31]([CH3:32])([CH3:39])[N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:35]([CH3:36])([CH3:37])[CH2:11]2)[CH2:2][C:35]1([CH3:36])[CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCC1=C(CC)C2CCC1C2
Reactant: CCCCCCCCCCCCCCCCCCN1C(C)(C)CC(O)CC1(C)C
Product: CCCCCCCCCCCCCCCCCCN1C(C)(C)CC(C2=C(C3CC(C)(C)N(CCCCCCCCCCCCCCCCCC)C(C)(C)C3)C3CCC2C3)CC1(C)C

Procedure:
In an analogous manner is also reacted diethyl bicyclo [2.2.1]hept-5-ene-endo,exo-2,3-dicarboxylate with 1-n-octadecyl-2,2,6,6-tetramethyl-4-piperidinol to give wax-like bis-(1-n-octadecyl-2,2,6,6-tetramethyl-4-piperidyl) bicyclo[2.2.1]hept-5-ene-endo,exo-2,3-dicarboxylate. (Example 9)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:28])(=[O:27])[NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:28])=[O:27])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Yield: 78.9 %

Procedure:
Prepared using general procedure 28, method B. Under N2 atmosphere, a solution of tert-butyl-1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate (3 g, 7.02 mmol) in 4 M HCl/dioxane (100 mL) was stirred at RT for 16 h. The formed precipitate was filtered off and washed with dioxane (20 mL) to give 4-(4-aminopiperidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (1.88 g, 81%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340; tR=1.28 min.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1>C1COCC1>[NH2:30][C@@H:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[CH:9][CH:10]=2)=[CH:20][CH:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 119.4 %

Procedure:
Trifluoroacetic acid (5.5 g) is added dropwise to a stirred suspension of (S)-3-[4-(quinolin-4-yloxy)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.76 g, 1.88 mmol) in THF (2 mL) while cooling with an ice bath. The mixture is stirred at rt for 3 days, then it is concentrated under reduced pressure. The residue is treated with ethyl ether to give the title compound (0.692 g, 87%) as a trifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:27])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(NS(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 2 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]methanesulfonamide (0.097 g, 0.256 mmol) in DMF (2 mL) was added Cs2CO3 (0.083 g, 0.256 mmol) and MeI (0.04 g, 0.28 mmol, dissolved in DMF). After stirring for 2 hours, additional MeI (0.02 g, 0.14 mmol) was added. The product mixture was concentrated. The residue was partitioned between CHCl3 and pH 7 buffer. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:23]>C(Cl)Cl>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:22](=[O:23])[O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Temperature: 25 °C

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.6 mmol) in 5 mL CH2Cl2 was added triethylamine (0.73 mL, 5.2 mmol), and the reaction was cooled to −20° C. (S)-tetrahydrofuran-3-yl chloroformate (525 mg, 3.48 mmol) was added in portions over a period of 10 minutes to the above reaction mixture. After allowing the reaction to warm to room temperature, it was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 63%). LC/MS: m/z 301.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]Br)=[O:5])[CH3:2].[CH2:24]([N:26](CC)[CH2:27][CH2:28]N)[CH3:25]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:5])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c(CCCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C

Procedure:
5-(4-Bromo-butyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60c (220 mg, 0.57 mmol) was dissolved in 5 ml of dichloromethane under stirring, and added with N,N-diethylethylenediamine (164 μl, 1.13 mmol) to the solution and refluxed for 30 minutes in an oil bath. The reaction mixture was concentrated to evaporate solvent and refluxed for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-(4-diethylamino-butyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-cert-butyl ester 4-ethyl ester 60d (187 mg, yield 78%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:12])[C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:12])[C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: C1COCCN1
Reactant: C[C@@H](OC1CCCCO1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
Anhydrous tetrahydrofuran (250 ml) was added to (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (32 g). To the mixture was added by portions 1,1'-carbonyl-diimidazole (35.8 g), with stirring at room temperature during 10 minutes. The resultant mixture was stirred for 30 minutes at room temperature and, then, cooled with ice, to which was added dropwise morpholine (38.3 g) during 15 mintues, followed by stirring for 15 minutes in an ice-bath. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in dichloromethane (300 ml). The solution was washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=1:4) to afford N-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (25.7 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].O1CCOCC1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)#[N:2]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1I
Reactant: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 90 °C
Yield: 81.7 %

Procedure:
To a 500 mL RBF containing ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (17.20 g, 44.65 mmol, prepared as in WO 2009154741) was added anhydrous 1,4-dioxane (172.0 mL, 2204 mmol). To the resulting suspension was added morpholine (8.177 mL, 93.77 mmol). A reflux condenser was attached and the pink/orange heterogeneous suspension was heated to bath temp 90° C. and allowed to stir. Shortly after heating began, reaction mixture became a cherry red, homogenous solution. Reaction was stirred for 16 hours at 90° C. The reaction was then cooled to room temperature and diluted with water (100 mL). Mixture was filtered, and the solid was dried for in vacuo at 40° C. for 5 days to afford ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (14.3 grams, 82% yield). LCMS: (FA) ES+ 393; 1H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1, 2H), 3.78-3.70 (m, 4H), 3.63-3.57 (m, 4H), 1.26 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: BrCc1ccccc1
Reactant: OCC1CC(Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClC1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 3-chlorocyclobutanemethanol (17.3 g, 0.143 mole) and benzylbromide (29.96 g, 0.1576 mole) in dry dimethylformamide (123 ml) was stirred at room temperature under an argon atmosphere and a 60% suspension of sodium hydride (6.31 g) was added. The reaction was stirred at ambient temperature for 22.5 hours. The reaction mixture was poured into 600 ml of water and the aqueous mixture extracted with ethyl acetate (4×500 ml). The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate and the ethyl acetate evaporated in vacuo yielding the crude product as a yellow oil. The material was purified on a 2-liter Merck silica gel column eluting with 3 liters of hexane, followed by 5% ethyl acetate/hexane. The fractions containing the desired product were combined and the volatiles evaporated in vacuo yielding 28.6 g of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C@H:10]2[C@H:5]([C@@H:6]3[CH2:11][C@H:9]2[CH:8]=[CH:7]3)[C@@H:4](N[C@@H](CC(C)C)C(OCC2C=CC=CC=2)=O)[O:3]1.[OH2:28]>>[OH:28][C@@H:4]1[C@@H:5]2[C@@H:10]([C@H:9]3[CH2:11][C@@H:6]2[CH:7]=[CH:8]3)[C:2](=[O:1])[O:3]1
Reactant: O
Reactant: CC(C)C[C@H](N[C@H]1OC(=O)[C@H]2[C@@H]1[C@H]1C=C[C@@H]2C1)C(=O)OCc1ccccc1
Product: O=C1O[C@H](O)[C@@H]2[C@H]1[C@@H]1C=C[C@H]2C1
Temperature: 55 °C

Procedure:
2.2 g of the product of Step A were added to a mixture of 1.8 ml of 22° Be hydrochloric acid in 18 ml of water and the mixture was heated at 55° C. for 17 hours and was then cooled to 20° C. The mixture was extracted with ethyl acetate and the organic phase was washed with 2N aqueous sodium hydroxide solution. The alkaline aqueous phase was washed with methylene chloride, with ethyl acetate and was acidified to a pH of 3.5 by addition of 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was taken up in ether and the mixture was vacuum filtered to obtain 0.450 g of (3S,3aS,4R,7S,7aR) 3-hydroxy-3a, 4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one melting at 133° C. and having specific rotation of [α]D20 =- 44° (c=1% in benzene).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:10]([CH2:28][S:29][C:30]2[NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]=2)=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1([CH3:27])[O:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][O:18]1.ClC1C=CC=C(C(OO)=[O:47])C=1>CO>[CH3:8][C:9]1[C:10]([CH2:28][S:29]([C:30]2[NH:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=2)=[O:47])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1([CH3:27])[O:18][CH2:19][C:20]2([O:21][CH2:22][CH2:23][O:24]2)[CH2:25][O:26]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
To a toluene (8.1 ml) and methanol (0.9 ml) solution of the 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (372 mg, 0.84 mmol) obtained in the step (5f), a toluene (2.7 ml) and methanol (0.3 ml) solution of 3-chloroperbenzoic acid (200 mg, 0.76 mmol as the content was regarded as 65%) was added dropwise at −55° C. to −50° C. for 10 minutes in a nitrogen atmosphere. The mixture was stirred at −60° C. to −50° C. for 1.5 hours. The reaction was terminated by adding 12 ml of a saturated aqueous solution of sodium hydrogen carbonate at the same temperature. The mixture was extracted with 50 ml of chloroform twice, and then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and desired fractions were concentrated. The obtained white foam was re-precipitated with chloroform and diethyl ether and filtered. The operation was repeated twice to obtain the title compound (148 mg, 38.4% yield) as a white solid.
Reaction SMILES: C1(S[CH:8]=[CH:9][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])C=CC=CC=1.C([O:29][C:30]1[CH:35]=[CH:34][C:33](C2C=CC=CC=2)=[CH:32][CH:31]=1)(=O)C#C.C1(O)C=CC=CC=1>>[O:29]([CH:8]=[CH:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Solvent: Oc1ccccc1
Product: O=C(C=COc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Yield: 80 %

Procedure:
The compound 6 was prepared according to the method described for compound 4 employing compound 1 (435 mg, 2.15 mmol) and phenol (223 mg, 2.36 mmol) to give white solid compound 6 (510 mg, 80%). 1H NMR (300 MHz, CDCl3) δ 5.67 (d, J=12.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.33 (q, J=7.9 Hz, 5H), 7.49 (t, J=7.0 Hz, 5H), 7.92 (d, J=12.2 Hz, 1H). HRMS ESI (m/z): Calculated for C21H16O3 ([M+H]+): 317.1099. found: 317.1175.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:9]([NH2:10])=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][C:5]=1[S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15].[H][H]>O.C(O)C.[Ni]>[NH2:11][C:7]1[CH:8]=[C:9]([NH2:10])[C:4]([CH2:3][CH2:2][NH2:1])=[C:5]([S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])[CH:6]=1
Reactant: [H][H]
Reactant: NCCc1c(N)cc([N+](=O)[O-])cc1S(=O)(=O)CCC(=O)O
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: NCCc1c(N)cc(N)cc1S(=O)(=O)CCC(=O)O
Temperature: 60 °C

Procedure:
27.0 g of 3-[2-(2-aminoethyl)-amino-5-nitrophenylsulphonyl]-propionic acid are suspended in 150 ml of water and 150 ml of ethanol. In an autoclave 1 g of nickel is added to the suspension, 60-70 bar of hydrogen are injected, and the temperature is raised to 60° C. Stirring is continued for some time until no further hydrogen is absorbed. After letting down, the resultant solution is clarified at 70° C. with 1 g of activated charcoal, the clarification residue is washed with 20 ml of hot water, and the combined filtrates are reacted as per Example 10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[N:38]=[CH:37][N:36]=[C:35]([O:39][C:40]2[C:45]3[N:46]=[C:47]([NH:49][C:50](=[O:52])[CH3:51])[S:48][C:44]=3[CH:43]=[CH:42][CH:41]=2)[CH:34]=1>>[C:50]([NH:49][C:47]1[S:48][C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([O:39][C:35]3[N:36]=[CH:37][N:38]=[C:33]([C:24]4[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:28][C:23]=4[NH:22][C:19]([C@@H:9]4[CH2:10][CH2:11][C@H:12]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:8]4[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:20])[CH:34]=3)[C:45]=2[N:46]=1)(=[O:52])[CH3:51]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4C(=O)OC(C)(C)C)ncn3)cccc2s1

Procedure:
(2S,5R)-1-(tert-Butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (350 mg, 1.2 mmol, Neosystem-T) was reacted with N-(4-(6-(2-amino-4-(trifluoromethyl)-phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (446 mg, 1.0 mmol, prepared as described in WO04014871) under the conditions of Example 45(a) to give the title compound as a white solid. MS (ESI, neg. ion.) m/z: 719 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[S:6].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>CC(C)=O>[Cl:12][CH2:13][C:14]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[S:6][CH:16]=1
Reactant: NC(=S)c1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: ClCc1csc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-dichlorothiobenzamide (8.24 g., 0.04 mol), 1,3-dichloroacetone (5.1 g., 0.04 mol) in acetone (150 ml) was stirred at room temperature overnight. After evaporation of the acetone under reduced pressure, the residue was dissolved in methanol (150 ml) and the solution refluxed 11/2 hours. After cooling and removal of the methanol, the residue was slurried with a small quantity of methanol. The solids which formed after filtration showed m.p. 93°-96° C. (6.05 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl.CO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:26])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cncc(C(=O)O)c2)c(F)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)c[n+]([O-])c2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 5-(2-fluoro-4-methylphenyl)nicotinic acid (0.15 g, 0.43 mmol) in dichloromethane (5 mL) and methanol (3 mL) was added 3-chloroperbenzoic acid (70%; 0.16 g, 0.65 mmol). The mixture was stirred at ambient temperature. After 18 h, additional 3-chloroperbenzoic acid (70%; 0.19 g, 0.86 mmol) was added. The mixture was continued to stir at ambient temperature. After 24 h, additional 3-chloroperbenzoic acid (70%; 0.19 g, 0.86 mmol) was added. After 18 h, the mixture was concentrated. Purification by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (70 mg). MS 248.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (700 mg, 1.52 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). Then sodium hydride (300 mg, 12.50 mmol, 8.25 equiv) was added. The resulting mixture was stirred for 1 h at room temperature. To this was added CH3I (0.5 mL) at 0° C. The resulting solution was stirred 3 h at room temperature. The reaction was then quenched by the addition of icewater. The resulting mixture was concentrated under vacuum. This resulted in 0.65 g (93%) of 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as yellow oil.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH3:3]
Reactant: CCI
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Iodoethane (3.35 mL, 41.4 mmol) was added slowly to a mixture of methyl 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (12.90 g, 27.6 mmol) and cesium carbonate (27.0 g, 83 mmol) in dimethyl sulfoxide (150 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with methylene chloride. The phases were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified via column chromatography (ISCO, 330 g silica, 0-20% ethyl acetate/methylene chloride) to afford a solid residue that was triturated from methanol to give methyl 7-(ethyloxy)-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (11.39 g, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.98-8.04 (m, 2H), 7.91 (d, J=7.78 Hz, 1H), 7.76-7.82 (m, 2H), 4.39 (q, J=7.03 Hz, 2H), 4.09 (s, 3H), 3.85 (quin, J=6.84 Hz, 1H), 2.36 (s, 3H), 1.44 (t, J=7.03 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H); MS (m/z) 496.1 (M+H+).