Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Temperature: 99 °C
Yield: 46.4 %

Procedure:
Add to a 300 mL of autoclave reactor (s)-(+)-2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (12.46 g, 0.05134 mol), bis(dibenzylideneacetone)palladium (0) (2.35 g, 0.002567 mol), 2-di-tert-butylphosphino biphenyl (1.53 g, 0.005134 mol) and sodium methanesulfonamide (12.02 g, 0.1027 mol) in toluene (250 mL). Flush with nitrogen 3 times and heat to 99° C. for 24 h. Filter and dissolve the filter cake in water (400 mL). Extract the aqueous layer with chloroform (3×200 mL), dry (magnesium sulfate) and concentrate. Dissolve the crude product in dichloromethane (20 mL) and precipitate out by adding hexanes (400 mL) to give a solid (7.18 g, 46%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)=[CH2:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[CH2:2]
Reactant: C=Cc1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To the solution of 3-vinyl benzaldehyde (5 g, 38 mmol) and morpholine (3.0 mL, 52 mmol) in dichloromethane (126 ml) was added sodium triacetoxyborohydride (19.2 g, 92 mmol) in portion at 0° C. followed by acetic acid (2.3 mL, 40 mmol). After the addition, reaction mixture was raised to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane washed with 1N NaOH and extracted with dichloromethane 3 times. The combined organic layer was dried over magnesium sulfate and concentrated under vacuum to give the title compound as pale yellow oil (7.2 g, 93% yield)
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:44][O:45][CH3:46].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:28][CH:29]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:44][O:45][CH3:46])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCc1cc2c(=O)n(CC(=NOC)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)methane hydrochloride (0.086 g), pyridine (5 mL) and ethanol (5 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.15 g, 73%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH2:56]([CH:61]=O)[CH2:57][C:58]([OH:60])=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:61][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCCC(=O)O)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 45.1 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with succinic semialdehyde (76.6 mg, 6.0 eq) to provide the title barbituric acid (50.0 mg, 45%). MS found: (M+H)+=546.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C.C(Cl)Cl.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)=[O:20])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CBr)N1CCc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: CC#N
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO 3 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Cl:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Product: O=[N+]([O-])c1ccc(OCCCl)cc1

Procedure:
4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo . After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro-(2-chloroethoxy)benzene (909 mg).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([NH:5][NH2:6])=O.[I:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:13](=[NH:17])OCC>CO>[I:9][C:10]1[CH:11]=[C:12]([C:13]2[NH:17][C:3]([C:2]([F:8])([F:7])[F:1])=[N:5][N:6]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: NNC(=O)C(F)(F)F
Reactant: CCOC(=N)c1ccc(C)c(I)c1
Solvent: CO
Product: Cc1ccc(-c2nnc(C(F)(F)F)[nH]2)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
2,2,2-Trifluoroacetohydrazide (0.14 g, 1.0 mmol) was added to a stirred solution of ethyl 3-iodo-4-methylbenzimidate (preparation 51b, 0.30 g, 1.0 mmol) in methanol (3 mL) and the mixture was stirred and heated to 70° C. After 2 hours, the mixture was cooled and concentrated in vacuo. The residue was purified by flash chromatography (5:1 hexanes/ethyl acetate) to give the title compound (0.10 g, 27%) as a white solid.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>>[CH2:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][CH2:23][S:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]1)[CH2:35][CH3:36]
Reactant: CCCc1ccccc1OCCCCBr
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1ccccc1OCCCCSCC1COC(CCC(=O)OCC)(CCC(=O)OCC)S1

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0 g, 0.006 mol), the bromide produced in Example 22 (1.63 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g). The crude product was chromatographed on silica gel using 15% ethyl acetate/hexane as eluent to give 2.78 g (87%) of the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.I[CH:30]([CH3:32])[CH3:31]>C(#N)C.C(Cl)Cl>[CH:30]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][CH2:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:28])[N:9]3[CH3:27])=[CH:4][C:3]=2[O:2][CH3:1])[C@@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:32])[CH3:31]
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CC(C)I
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(C)C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Yield: 34.7 %

Procedure:
6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.26 mmol) and 2-iodopropane (0.058 mL, 0.58 mmol) were stirred in acetonitrile at 60° C. for 2 days. The reaction was diluted with methylene chloride, washed once with satd. NaHCO3, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (9.1 ethyl acetate/methanol) gave 38 mg (34%) of the title compound, a yellow oil. Rf=0.08 (9:1 ethyl acetate/methanol). MS (M+H)+=422.1; 1H NMR (400 MHz, CDCl3): δ 0.66–0.68 (d, J=6.5 Hz, 3H), 1.00–1.02 (d, J=6.5 Hz, 3H), 1.35–1.42 (m, 1H), 1.50–1.53 (bd, J=13.0 Hz, 1H), 1.91–1.97 (m, 1H), 2.02–2.07 (m, 1H), 2.22–2.28 (t, J=11.5 Hz, 1H), 2.53–2.57 (t, J=7.4 Hz, 2H), 2.64 (s, 1H), 2.75–2.79 (t, J=7.4 Hz, 2H), 2.94–3.02 (m, 2H), 3.12 (s, 3H), 3.38–3.42 (d, J=14.6 Hz, 1H), 3.54 (s, 3H), 3.60 (s, 1H), 3.66–3.69 (d, J=14.6 Hz, 1H), 6.49 (s, 1H), 6.66 (s, 1H), 7.19–7.29 (m, 3H), 7.36–7.38 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 12.0, 20.3, 21.1, 25.5, 27.7, 29.6, 31.8, 44.1, 45.0, 48.5, 55.5, 56.3, 109.8, 112.8, 116.0, 124.9, 126.7, 127.8, 129.2, 133.5, 141.5, 152.9, 170.0. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18]([O:20]CC)=[O:19])[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[C:18]([OH:20])=[O:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Temperature: 120 °C
Yield: 88.1 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (1.00 g, 2.93 mmol), in 2:1 tetrahydrofuran:methanol (15 mL) was added 1 N aqueous sodium hydroxide (4.40 mL, 4.40 mmol). The solution was heated in a microwave reactor to 120° C. for 500 seconds. Then 1 N aqueous hydrochloric acid (4.40 mL, 4.40 mmol) was added and the solution was concentrated. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and dried under a nitrogen stream at 45° C. overnight to afford 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl) -4-isoxazolecarboxylic acid (808 mg, 88%). 1H-NMR (400 MHz, DMSO-d6) δ 13.34 (br s, 1H), 8.81 (s, 2H), 4.33-4.25 (m, 1H), 2.42-2.32 (m, 4H), 2.15-2.05 (m, 1H), 1.96-1.88 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31](O)=[C:30]([F:35])[CH:29]=1.C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:22][CH:15]([C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:30]([F:35])[CH:29]=1
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC(Oc1ccc(C(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
Combine 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptan-1-ol (0.050 g, 0.15 mmol) and 3-fluoro-4-hydroxy-benzoic acid methyl ester (0.030 g, 0.18 mmol) in toluene (0.5 mL). Add 1,1′-(diazocarbonyl)dipiperidine (0.057 g, 0.23 mmol) followed by tributyl-phosphine (0.06 mL, 0.23 mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-40% ethyl acetate/hexane gradient) to provide 0.04 g of title compound (57%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:19]1[C:2]2([CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]2)[O:1][CH2:17][CH2:18]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Temperature: 120 °C

Procedure:
A mixture of benzyl 3-oxopyrrolidine-1-carboxylate (2.00 g), ethane-1,2-diol (2.85 mL), p-toluenesulfonic acid monohydrate (10 mg) and toluene (20 mL) was stirred with heating in a Dean-Stark apparatus at 120° C. for 6 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 mL), washed successively with water (5 mL×2) and brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g) as a pale-yellow liquid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH2:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.O>[NH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][S:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH:20]2[C:19]3[C:24](=[C:25]([Cl:27])[CH:26]=[C:17]([Cl:16])[CH:18]=3)[CH2:23][N:22]([CH3:28])[CH2:21]2)[CH:30]=1)(=[O:37])=[O:36]
Reactant: NCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCN)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol, 5.52 equiv) in DMF (20 mL), potassium carbonate (2.0 g, 14.39 mmol, 14.05 equiv) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (400 mg, 1.02 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature at which time it was diluted with 100 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers were combined and dried over sodium sulfate and concentrated under vacuum. This resulted in 60 mg (13%) of N-(2-(2-aminoethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([O:19][CH3:20])=[N:12][CH:13]=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl.C[O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25]>>[CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:14]([C:15]([NH:35][C:26]3([C:24]([OH:25])=[O:23])[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:34]3)=[O:17])[CH:13]=[N:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ncc(C(=O)O)cc1-c1cccc(C(C)C)c1
Agent: Cl
Product: COc1ncc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1-c1cccc(C(C)C)c1

Procedure:
The compound of step 2 was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13, and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C(C)C)C=CC=CC=1>O>[CH2:10]([N:17]1[C:5](=[O:6])[CH2:4][C@H:2]([OH:3])[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: CC(C)c1ccccc1
Solvent: O
Product: O=C1C[C@H](O)C(=O)N1Cc1ccccc1
Yield: 39.6 %

Procedure:
A mixture of 50.0 g (0.373 mole) (S)-malic acid (Ia), 41 ml (0.373 mole) benzyl amine and 250 ml cumene was heated with an internal temperature of 155° C. for 2.5 h on a water separator, during which time 12 ml water were separated. An oily phase formed during cooling off which slowly crystallized. The cumene was decanted off thereafter and the residue crystallized out of 220 ml EtOH. 30.3 g (39.6%) (S)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (IIa) were isolated in the form of colorless crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: c1cscn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12f and thiazole
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:20])[CH:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[C:24](=[O:31])[N:23]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C1(C)C=CC=CC=1.O>[F:20][C:4]1[CH:3]=[C:2]([NH:1][C:28]([C:25]2[C:24](=[O:31])[N:23]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:22]([CH3:21])[C:26]=2[CH3:27])=[O:29])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)quinolin-7-ol (10 g, 37.0 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (10 g, 44.4 mmol), HOAT (0.5 g, 3.7 mmol) in DMF (50 mL) and toluene (30 mL) was added EDCI (8.5 g, 44.4 mmol). The reaction was stirred at 45° C. overnight, then diluted with water (100 mL) and continued to stir at room temperature for 2 hours. The solid was collected through filtration, washed with a mixture of 95% EtOH (50 mL) and DCM (25 mL), and then treated with 3 M hydrochloric acid (10.5 mL). The resulted solid was collected and was recrystallized in a mixture of 95% EtOH and H2O (90 mL, EtOH/H2O=5:1, v/v) to give the title compound as a white solid (11.7 g, 60.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH3:12])[C:13](=[O:15])[CH:14]=[C:7]2[OH:9]
Reactant: CNc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)cc(O)c2cc(Cl)ccc21

Procedure:
5-Chloro-N-methyl anthranilic acid (15g; 0.081 mole) was dissolved in acetic acetic acid (41 ml) and acetic anhydride (41 ml) and the dark mixture refluxed for 12 hours. After cooling the red solution was poured onto crushed ice, basified with 2.5N sodium hydroxide solution and filtered free of tar. The filtrate on acidification to pH5 gave the carbostyril as a yellow solid, m.p. (AcOH) 317°-318°C (Found; C, 57.39; H, 3.98;N, 6.83; Cl, 16.69; C10H8NClO 2 requires C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[S:3][C:4]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:23])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1Sc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)sc1S(=O)c1ccccn1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 52.1 %

Procedure:
A mixture of 2-amino-4-methyl-5-(2-pyridylthio)thiazole (1.7 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (20 ml) and dichloromethane (50 ml) was stirred at 5° C. for 3.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyridylsulfinyl)thiazole (0.95 g, yield: 52.2 %). mp: 190°-193° C. (dec.)