Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([NH:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([O:17][CH2:14][CH2:15][CH3:16])[CH:19]=3)=[O:27])[CH2:29][CH2:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCOc1cc(F)cc(NC(=O)N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[[(3-propoxy-5-fluorophenyl)amino]carbonyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)-sulfonyl]-4-[[(3-propoxy-5-fluorophenyl)amino]-carbonyl]piperazine.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl[CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[C:19]([CH:34]=[CH:33][CH:32]=1)[CH2:18][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([CH2:36][CH2:37][CH2:38][N:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[C:40]3[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCCl
Reactant: O=C(OCc1ccccc1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCN1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCc3ccccc3)c1)CN2c1ccccc1
Temperature: 81 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
A mixture of benzyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (807 mg, 1.65 mmol, 1 equiv), tert-butyl 1-(3-chloropropyl)-1H-indole-2-carboxylate (507 mg, 1.65 mmol, 1 equiv), sodium iodide (123.3 mg, 0.823 mmol, 0.5 equiv) and potassium carbonate (684.1 mg, 4.95 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.2, gradient—10%-50% ethyl acetate in hexanes) to afford the title compound as an oil (230 mg, 19%); MS for C44H48N4O5 m/z 713.37 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:1]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=3[CH2:4][CH2:3][C:2]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCC2=C(CCCC2=O)N1
Reactant: ClCc1ccc(Cl)cc1
Product: O=C1CCCC2=C1CCC(=O)N2Cc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 29 from 3,4,7,8- tetrahydro-2,5(1H,6H)-quinolinedione and 4-chlorobenzyl- chloride.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[O:14][C:12]1[CH:13]=[C:8]([CH:9]=[CH:10][C:11]=1[F:15])[NH2:7]
Reactant: Nc1ccc(F)c(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred slurry of cesium carbonate (9.53 g, 29 mmol) in a mixture of THF/DMF (9/1, 200 mL) at rt, was added 5-amino-2-fluorophenol (2.10 g, 14.6 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.61 g, 16 mmol) was added and the reaction mixture was heated at 50° C. for 30 h. The reaction was cooled to rt, then diluted with ethyl acetate. The solution was washed with 1 N sodium hydroxide solution, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with methanol. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (3.10 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (dd, J=9.2, 9.2 Hz, 1H), 6.47-6.56 (m, 2H), 5.19 (brs, 2H), 4.00 (s, 3H), 3.99 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[OH:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[O:27][C:14]1[CH:13]=[CH:12][C:4]([C:5]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CC(C)CNC(=O)c1ccc(F)c(Cl)c1
Product: CC(C)CNC(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:36]5[CH2:37][CH2:38][CH:33]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)[CH2:34][CH2:35]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCC(N2CCCC2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 4-(pyrrolidin-1-yl)piperidine via General Procedure B. The product was purified via reverse phase HPLC to give 13.2 mg of 249. MS (Q1) 517.8 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.CCCCCC.[B:23]([O:32]C(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1.CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:24][B:23]([OH:32])[OH:28])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(OB(O)O)cc1
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
13.09 g of 4-Bromoanisole was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to -78° C. with a dry ice-acetone freezing mixture, and 48 ml of m-butyllithium (as a 1.6 M hexane solution). The mixture was stirred for 10 minutes. A tetrahydrofuran solution of 32 ml of triisopropyl borate was added dropwise under cooling over the course of 30 minutes. The temperature of the solution was returned to room temperature, and it was stirred for 10 minutes. Ether was added to the reaction solution, and it was washed with a 10% aqueous solution of hydrochloric acid and water in this order. The solvent was evaporated, and the resulting solid was recrystallized from ether-hexane to give 7.18 g (yield 67.5%) of (4-methoxyphenyl)boric acid as colorless needles having a melting point of 157° to 159° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
As in Example 115, (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid (1 g) and 4-nitrophenol (0.54 g) in 7 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (0.67 g). The mixture was stirred at room temperature for 2 hours. After the usual work up, the crude ester was crystallized from 2-propanol to give 0.825 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 133.5°-135° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6]1.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[N+](CC)([O-])=O>[CH:5]1([C:9]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:11])[CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccccc1
Reactant: O=C(O)C1CCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: COc1ccc(C(=O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of AlCl3 (13.4 g) in nitroethane (25 ml) was added to a solution of cyclobutane carboxylic acid (10.0 g) and anisole (10.8 g) in nitroethane (75 ml) at 10° C. The mixture was stirred for 5 hours at room temperature, was than poured on ice and extracted with MTBE. The organic phase was washed with aqueous sodium hydroxide, water and brine, dried (MgSO4) and concentrated in vacuo. The essentially clean ketone (10.8 g) was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH:24]=O)[CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)[CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(CC(=O)N1CCc2ccccc2C1)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
2-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1,2,3,4-tetrahydroisoquinoline (800 mg), in MeOH/THF (1:1, 20 mL) was treated sequentially with molecular sieves 3A (900 mg), 4-phenyl-4-hydroxypiperidine HCl (900 mg) and NaBH3CN (130 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (810 mg). Mass spectrum (FAB): 537.2075.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2cccnc2)c1
Yield: 66 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 3-pyridineboronic acid, the expected product is obtained in the form of a light brown powder with a yield of 66%.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CCC3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To a 250-mL round bottom flasked is added 10% Pd/C (100 mg). The flask was sealed with a septum, and flushed with a slow stream of N2. 1-Cyclobutyl-4-(4-nitrophenyl)piperazine (1 g, 3.83 mmol) was dissolved in EtOH (30 mL) and transferred via syringe into the flask. The flask is again flushed with N2 and then it is fitted with a balloon of hydrogen. An outlet needle is inserted through the septum and the flask is flushed with hydrogen before the outlet needle is removed. The resulting slurry is stirred vigorously under the H2 atmosphere at rt. After 24 h the yellow color of the solution dissipates and the hydrogen balloon is removed. The flask is flushed with nitrogen, DCM (10 mL) is added to the reaction mixture, and the resulting slurry is stirred at rt for 1.5 h. The reaction is filtered through a filtration tube packed with a short column of Celite, the Celite washed with DCM (2×20 mL), and the combined filtrate evaporated to dryness on a rotary evaporator. The product is air dried for 48 h and then dried under vacuum for 2 h to provide crude 4-(4-cyclobutylpiperazin-1-yl)aniline (0.87 g, 98% recovery, 100% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C14H21N3, 231; [M+H]+ found, 232.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[N:3]=1.CCCCCC.C([Li])CCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].O>O1CCCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1
Reactant: COCOCc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(COCOC)n1
Temperature: -67.5 °C
Reaction time: 0.83 h
Yield: 123.7 %

Procedure:
Under a stream of argon, compound (11) (24.7 g; 106 mmol) was dissolved in anhydrous tetrahydrofuran (270 mL), and 1.54M n-butyllithium hexane solution was added dropwise thereto over 50 minutes at −65 to −70° C. The resulting reaction mixture was stirred at −65 to −70° C. for 1 hour. To the reaction mixture, tetrahydrofuran solution of 40 g (122 mmol) of tributyltin chloride (100 mL) was added dropwise over 30 minutes. While gradually raising the temperature of the reaction solution (to −20° C.), the reaction mixture was stirred at −20° C. for 20 hours. To the reaction mixture, water (250 mL) was added, and the resulting mixture was extracted with diethyl ether three times. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 58 g of the crude title compound (12). The obtained compound was used in the next step without further purifying.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[C:7]1=[O:26])=O)C.[CH3:27][NH2:28].O>CN(C)C=O.C(O)C>[CH3:27][NH:28][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[C:7]1=[O:26])=[O:3]
Reactant: CN
Reactant: CCOC(=O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Temperature: 120 °C
Yield: 14 %

Procedure:
300 mg (0.84 mmol) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester is dissolved in 2 ml N,N-dimethylformamide. 0.17 ml (4.2 mmol) of a 33% solution of methylamine in ethanol is added. The reaction vessel is tightly stoppered and heated to 120° C. for 24 hours. Addition of water precipitates the crude material. Chromatography (silica gel, dichloromethane/methanol) yields 41 mg (14%) of a yellowish solid. MS: m/e=343.2 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 82 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 82% of theory, C26H25N5O4 (471.5) Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) ##EQU33##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:15]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21]
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: O=C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 μmol) tris-(dibenzylideneacetone)-dipalladium (0), 67.1 mg (116 μmol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95° C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative)
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]([CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=O)[NH2:13].Cl>O1CCCC1.CO>[NH2:13][CH2:12][CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h

Procedure:
To a suspension of sodium borohydride (0.30 g) in tetrahydrofuran (15 ml) was added boron trifluoride etherate (3.5 ml) in a nitrogen stream with stirring at 0°-5° C. The mixture was stirred at the same condition for 30 minutes. To the mixture was added a solution of (2S, 4R)-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.60 g) in tetrahydrofuran (3 ml) at 0°-5° C. The mixture was stirred at 0°-5° C. for 1 hour and at ambient temperature overnight. Methanol (10 ml) was added to the reaction mixture at 0°-10° C. After 2 hours, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. A solution of the residue in a mixture of concentrated hydrochloric acid (3 ml) and methanol (30 ml) was stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure to give (2S, 4R)-2-[(2-aminoethyl)oxymethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. To a solution of the compound above in a mixture of water (10 ml) and tetrahydrofuran (20 ml) was added a solution of potassium cyanate (1.50 g) in water (5 ml) at 40°-45° C., keeping the pH between 4-5 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.38 g).
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:23](=[O:26])[CH2:24][CH3:25])([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CCC(=O)Cl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)CC
Yield: 77.1 %

Procedure:
Using the method of Example 68, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 595 mg, 2.00 mmol) was reacted with propionyl chloride (463 mg, 5.00 mmol). The crude product was purified by IFC (silica gel eluting with a gradient of 15 to 25% CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes to provide 545 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]propionamide as a white solid, mp 158-159° C. MS (APCI) m/z 354 (M+H)+; Anal. Calcd for C20H27N5O: C, 67.96; H, 7.70; N, 19.81. Found: C, 67.80; H, 8.08; N, 19.77