Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.O[CH:22]([C:28](C)=C)[C:23](OCC)=O.Cl.C[OH:33]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:33])[C:17](=[C:22]([CH3:28])[CH3:23])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CO
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 36.7 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (2.16 g, 15 mmol) and tetrabutylammonium chloride (278 mg, 1.0 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 1.5 hours. After completion of the reaction, the reaction solution was allowed to cool to 70 to 80° C., and a mixed solution consisting of methanol (5 mL) and 6N hydrochloric acid (0.25 mL) was added thereto and mixed homogeneously. Then, the reaction solution was left to stand at room temperature. The precipitated solid was collected by filtration, washed with a mixed solution consisting of methanol (8 mL) and 6N hydrochloric acid (0.4 mL) and then water (10 mL) and dried completely under reduced pressure to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.30 9, yield 36.7%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([OH:6])[C:3]1([CH3:8])[CH3:7].Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:6][C@H:4]1[CH2:5][C@@H:2]([NH:1][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[C:3]1([CH3:8])[CH3:7]
Reactant: CC1(C)[C@H](N)C[C@@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A mixture of (1S,3R)-3-amino-2,2-dimethylcyclobutanol (550 mg crude), 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (887 mg, 4.78 mmol) and DIEA (1.12 g, 8.7 mmol) in isopropanol (20 mL) was stirred at 85° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0.6% MeOH in DCM) to afford the title compound (760 mg, 2.88 mmol, 66.3% yield). MS (ESI) m/z 265.1 [M+1]+.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.CCN(CC)CC.[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>O.CC(C)=O>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4](=[O:11])[S:31]1
Reactant: CCOC(=O)CNCC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)CN1CC(C)C
Temperature: 40 °C
Yield: 20.3 %

Procedure:
A solution of N-isobutylglycine ethyl ester (0.41 g, 2.57 mmol) in water (5 mL) was treated with Et3N (0.71 mL, 5.15 mmol), followed by a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.50 g, 2.57 mmol) in acetone (5 mL). The resulting mixture waxs heated at 40° C. for 2 h, then cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (25 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-5-one (0.16 g, 88%): mp 152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].CN1CCOCC1.[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A stirred solution of methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (0.2 g.) in dichloromethane (5 ml. ) under an atmosphere of nitrogen, was treated with N-methylmorpholine (0.25 g.), followed by hexanoyl chloride (0.103 g.). After being stirred for 2 hours, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2×20 ml.). The combined organic extracts were dried (MgSO4) and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (75 ml.), eluting with 6:4 v/v ethyl acetate:hexane, to give the title compound (0.24 g., 92%) as a colorless oil; NMR: 0.83(t,3H, CH2.CH3), 1.36(m,4H, CH2.CH2.CH3), 1.57(quintet,2H, CH2.CH2.CON), 2.24(t, 2H, CH2.CON), 3.80(s,3H, COOCH3), 3.90(s,3H, OCH3), 3.99(s,2H, CH2. Ar), 7.1(m, 2H), 7.21(m,2H), 7.44(m,2H), 7.69(s,1H, H4 -indole), 9.59(s,1H, CONH), 10.77(s,1H, H1 -indole).
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([C:13]([CH:15]2[CH2:17][CH2:16]2)=O)[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19]>C(O)(C)(C)C>[CH:1]1([C:7]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[N:25]=[C:24]3[N:20]([CH2:18][CH3:19])[N:21]=[CH:22][C:23]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=CC1CCCCC1)C(=O)C1CC1
Reactant: CCn1nccc1N
Solvent: CC(C)(C)O
Product: CCn1ncc2c(C3CCCCC3)c(C(=O)OC)c(C3CC3)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3-cyclohexyl-2-(cyclopropylcarbonyl)acrylate (6.01 g) and 1-ethyl-1H-pyrazol-5-amine (2.97 mg) in tert-BuOH (60 ml) was refluxed for 22 hours. The solvent was evaporated off, and the residue was dissolved in dioxane (60 ml). To the mixture was added 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (5.77 g). The mixture was stirred for 6 h at room temperature. The mixture was filtered off, and the filtrate was evaporated. The residue was dissolved in EtOAc (20 ml), and to the solution was added silicagel, followed by hexanes (100 ml). The mixture was filtered, and filter cake was washed with EtOAc-hexanes (1-5). The filtrate was evaporated off. Silicagel column chromatography (EtOAc-hexanes, a linear gradient of EtOAc from 0 to 15%) afforded methyl 4-cyclohexyl-6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as a colorless oil, which was crystallized upon standing (4.36 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(C)(C)C.[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25]>C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O

Procedure:
Accordingly, the present invention also includes a process for the manufacture of these compounds. Such a process embraces in a first step the manufacture of a mixed anhydride and its conversion into quinargine as described above. The mixed anhydride, e.g. 2,2-dimethylpropionic acid-quinoline-2-carboxylic acid anhydride, can be obtained by adding an adjuvant base, e.g. triethylamine, to a mixture of quinoline-2-carboxylic acid and a reactive acid derivative, preferably pivaloyl chloride. The resulting mixed anhydride is subsequently reacted with asparagine in alkaline solution to give N-(2-quinolylcarbonyl)-L-asparagine. This substance is then converted in a subsequent step with 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)carboxamide into N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]-amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as described above or optionally into a corresponding salt, preferably the methanesulphonic acid salt, or into an ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), 4N aqueous sodium hydroxide solution (2.3 ml), tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and acidified with 10% aqueous citric acid solution, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (0.88 g, yield 95%) as colorless crystals. melting point >290° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:8]2)=[C:4](C)[CH:3]=1.[Cl:24]C1C=C(Cl)C=CC=1CN1C2C(=CC=CC=2)C(C(O)=O)=N1.ClC1C=CC(CN2C3C(=CC=CC=3)C(C(O)=O)=N2)=C(C)C=1>>[Cl:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:8]1
Reactant: O=C(O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)cc2C)c2ccccc12
Agent: Cc1cc(Cl)ccc1Cn1nc(C(=O)O)c2ccccc21
Product: CCOC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12

Procedure:
The product was obtained using the method described for the preparation of compound 10a, but using as reagent 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, prepared as described in J. Med. Chem. (1976) 19, 778-783, (0.4 mol) instead of 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH2:53])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.CN(C)C=O>[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH:53][C:7](=[O:9])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)SCCC(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
1.00 g of 3-(acetylthio)propionic acid, 1.39 g of dicyclohexyl carbodiimide, 1.05 g of 1-hydroxybenzotriazole and 1.76 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine were added to 45 ml of dimethylformamide, and the solution was stirred for 5 hours at room temperature. At the end of this time, ethyl acetate was added to the reaction mixture, insoluble matter was filtered off, and the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water. The reaction mixture was then condensed by evaporation under reduced pressure, and the resulting residue was subjected to silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 1.27 g (yield 48%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:20]>CN1C(=O)CCC1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:30][CH2:31]1)[CH3:20]
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccccc12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3nc(-c4ccccc4F)c4ccccc4n3)CC2)ccc1OC
Yield: 20.4 %

Procedure:
A solution of 2-chloro-4-(2-fluoro-phenyl)-quinazoline (38.8 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 14.9 mg (20%) of the title compound. MS (ISP): 487.5 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Ic1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(N2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (1.44 g, 5 mmol) and cyclopentanone (840 mg, 10 mmol) in DCE/THF (40 mL/20 mL) was added NaBH(OAc)3 (1.484 g, 7 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred 22 h at rt. After quenching with sat. NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), the solution was extracted with EtOAc (60 mL+30 mL). Removal of solvents, followed by trituration with MeOH afforded the crude title compound as a pale yellow solid (1.46 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.20 (t, J=4.8 Hz, 4H), 2.66 (t, J=4.6 Hz, 4H), 2.54 (p, J=7.6 Hz, 1H), 1.96-1.87 (m, 2H), 1.78-1.52 (m, 4H), 1.50-1.38 (m, 2H); MS ESI 357.0 [M+H]+, calcd. for [C15H21IN2+H]+ 357.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.COC(OC)OC.[BH4-].[Na+]>CO>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A suspension of tyramine (1 g; 7.29 mmol) in MeOH (8 ml) was treated with 4-trifluoromethyl benzaldehyde (1.27 g; 7.29 mmol) and trimethylorthoformate (5 ml). The reaction mixture was stirred at rt overnight and then treated with sodium borohydride (0.69 g; 18.23 mmol) in small portions. After stirring for 30 minutes, it was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Crystallization from ethyl ether-hexane provided the title compound as a white crystalline solid (1.67 g; 78% yield). 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.00 (d, 2H, J=8.4), 6.68 (d, 2H, J=8.4), 4.50 (bs, 2H), 3.86 (s, 2H), 2.88 (t, 2H, J=6.9), 2.77 (t, 2H, J=6.9).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][C:23]1[C:31]2[C:30]([CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]([CH2:42][CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])[C:34]3=[O:48])=[CH:29][S:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCCC2.Cl>O.C1COCC1>[C:1]([NH:47][S:44]([CH2:43][CH2:42][N:35]1[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:33]([CH2:32][C:30]2[C:31]3[C:23]([CH3:22])=[CH:24][CH:25]=[CH:26][C:27]=3[S:28][CH:29]=2)[C:34]1=[O:48])(=[O:46])=[O:45])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCS(N)(=O)=O)c4ccccc43)c12
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCS(=O)(=O)NC(=O)c4ccccc4)c4ccccc43)c12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Benzoic acid (6.1 mg, 0.050 mmol) is dissolved THF (0.50 mL) and 1,1′-carbonyl diimidazole (9.1 mg, 0.056 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid amide (10 mg, 0.025 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.007 mL, 0.050 mmol) is added. The mixture is stirred for 16 hr at room temperature. 1.0 M HCl solution (1.0 mL) is added followed by water (10 mL). The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 6% MeOH in EtOAc affords 11 mg (85%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid benzoylamide. LCMS (ESMS): m/z 506.25 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([O-])([O-])=O.[K+].[K+].C([O:22][CH2:23][CH3:24])(=O)C>CC(C)=O>[OH:12][C:5]1([CH2:13][C:23](=[O:22])[CH3:24])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CC1(O)C(=O)Nc2ccc(C)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Methylisatin 45 (10 mmol, Lancaster, order no. 8009) was dissolved in acetone 46 (50 ml), K2CO3 (138 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The course of the reaction was monitored by TLC (eluent: ethyl acetate). The reaction solution was worked up by concentrating to 40 ml in vacuo, during which the product started to precipitate. To complete the precipitation the solution was cooled to approx. 10° C. in a refrigerator overnight. The product which precipitated was filtered out with suction and dried in vacuo. It was possible to isolate further reaction product by removing the acetone completely and dissolving the residue which remained in ethyl acetate. The solid formed during subsequent precipitation with hexane was filtered out with suction and dried in vacuo.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([CH3:15])[O:13][C@@H:12]([OH:16])[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH3:20])C1C=CC=CC=1.O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].CC1C=CC(S(O)(=O)=O)=CC=1.[H][H]>C1C=CC=CC=1.CCO.[OH-].[OH-].[Pd+2].O>[OH:8][C@H:9]1[C@H:14]([CH3:15])[O:13][C@@H:12]([O:16][N:22]2[C:26](=[O:27])[CH2:25][CH2:24][C:23]2=[O:28])[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH3:20]
Reactant: [H][H]
Reactant: CO[C@@H]1[C@@H](OCc2ccccc2)[C@H](C)O[C@@H](O)[C@@H]1OC
Reactant: O=C1CCC(=O)N1O
Agent: [Pd+2]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CO[C@@H]1[C@@H](O)[C@H](C)O[C@@H](ON2C(=O)CCC2=O)[C@@H]1OC
Yield: 42.2 %

Procedure:
A solution of (2R,3R,4R,5S,6S)-5-benzyloxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-ol (10.5 g, 26.6 mmol, prepared according to Wu et al. Carbohydr. Res. 1998, 306, 493), N-hydroxysuccinimide (5.0 g, 50 mmol) and TsOH (250 mg, cat.) in 100 mL of benzene was heated at reflux for 24 h with removal of water using a Dean-Stark trap. The brown solution was cooled, filtered, washed with saturated sodium bicarbonate solution and concentrated. The gummy oil was purified by chromatography on silica gel, eluting with 70:30 hexanes:acetone. The pure O-succinimide (7.5 g, 14.5 mmol) was then transferred to a 500 mL Parr hydrogenation apparatus and debenzylated using 0.95 g of Pd(OH)2/C in 75 mL of EtOH. The solution, which took up 19 psi of hydrogen over 24 h, was then filtered and concentrated, leaving a solid residue which was recrystallized from EtOH to give 3.25 g of a white solid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([O:7][CH3:8])=[O:6].CO>O>[CH3:8][O:7][C:5](=[O:6])[C@H:4]([OH:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCC[C@@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 4.9 %

Procedure:
Lipase P-30 (Amano from Pseudomonas fluorescens) (1 g, 5% by weight) was dissolved in 140 ml of H2O and the pH of the solution adjusted to 7.5 with a 1N solution of NaOH. Racemic methyl 2-hydroxydecanoate (20.12 g, 0.995 mol) (CP-112,994) was added to the enzyme solution and the pH controlled to maintain a range of 6-8. The reaction was stirred at room temperature for 10 hours (total of 46.5 mL of 1N NaOH added) and worked up by addition of 140 ml of methanol. The aqueous alcohol was extracted with hexane (3×200 mL). The hexane extracts were combined and dried (MgSO4). Following concentration, the desired (R)-methyl-2-hyroxydecanoate (10.08 g, 0.049 mol, 50%) was obtained: [α]D =-3.1° (c=1, MeOH). The aqueous extracts were acidified to pH 1-2 with HCl and extracted with two portions of ethyl acetate (200 mL). The combined extracts were dried (MgSO4) and concentrated to give (S)-2-hydroxydecanoic acid (8.91 g, 0.047 mol, 47%): mp 70°-72°; [α]D =-1.7° (c=1, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[N:20][C:14]3[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].F[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:34]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[N:20][C:14]3[N:15]=[C:16]([NH:19][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:34])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3nc(N)ncc3c2)c1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-amine (400 mg, 1.42 mmol) in THF (20 mL) at 0° C. was added sodium hydride (102 mg, 4.25 mmol). The solution was stirred for 20 mins, followed by the addition of 2-fluoro-1-methyl-3-nitrobenzene (440 mg, 2.84 mmol). The reaction mixture was stirred at RT overnight, quenched by water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to afford 6-(3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (310 mg, 51%) as a brown solid. MS (ES+) C22H19N5O4 requires: 417. found: 418 [M+H]+.