Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:32])[N:4]([C:19]2[CH:27]=[C:26]([C:28]([NH:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=O)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl.[CH3:34][N:35](C)CCCC(N=C=N)C.ON1C2C=CC=CC=2N=N1.CN>CN(C=O)C.C(OCC)(=O)C.C(#N)C.O>[Br:1][C:2]1[C:3](=[O:32])[N:4]([C:19]2[CH:27]=[C:26]([C:28]([NH:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:20]=2[C:21]([NH:35][CH3:34])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(CCCN(C)C)N=C=N
Reactant: CNC(=O)c1ccc(C(=O)O)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C(=O)NC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reaction time: 16 h

Procedure:
To a room temperature solution of 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoic acid (500 mg, 0.986 mmol) in DMF (5.0 mL) was added 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HCl, 350.0 mg, 1.83 mmol) and 1-hydroxy-benzotriazole (HOBT, 100.0 mg, 0.74 mmol) sequentially. To this resulting suspension was then added a solution of methylamine (2.0 M THF, 1.0 mL, 2.0 mmol). The reaction was stirred for 16.0 hours, at which time the reaction was diluted with ethyl acetate (600 mL). The mixture was washed with (3×200 mL) of water and the organic extract was separated, Na2SO4 dried, and concentrated in vacuo to a volume of approximately 60 mL. At this time a solid precipitate formed and was collected to furnish (289 mg, 56%). 1H NMR (300 MHz, d4-MeOH) δ 8.06 (br d, J=8.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.73 (s, 1H), 7.70 (app q, J=7.4 Hz, 1H), 7.09 (app t, J=8.0 Hz, 2H), 6.65 (s, 1H), 5.39 (s, 2H), 2.96 (s, 3H), 2.79 (s, 3H), 2.13 (s, 3H); LC/MS C-18 column, tr=2.13 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 520 (M+H). ES-HRMS m/z 520.0700 (M+H calcd for C23H21BrF2N3O4 requires 520.0678).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1cccnc1
Yield: 42.4 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (74 mg, 0.42 mmol) gave the title compound (38 mg, 43%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH2:10][O:11][CH3:12])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH3:12][O:11][CH2:10][CH2:9][N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13]
Reactant: COCCn1c(N)c(N)c(=O)[nH]c1=S
Reactant: O=CO
Product: COCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 90 °C

Procedure:
5,6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.27 g, 1.3 mmol) was suspended in formic acid (2 mL) and this solution was heated at 90° C. for 1.5 h. Excess formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide solution (5 mL) was added to the orange solid and the resulting solution was heated at 90° C. for 2 h. The reaction mixture was neutralized with dilute acetic acid. The resulting solution was put in the fridge for several days, then the orange needle-like crystals that had formed were collected by filtration and washed with water. Yield: (0.11 g, 40%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl>[O:1]1[C:10]2[C:5](=[N+:6]([O-:19])[CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: c1cnc2c(c1)OCCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine (121 mg, 790 μmol) was dissolved in dichloromethane (4.0 mL), added 3-chloroperbenzoic acid (234 mg, 950 μmol), and stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol), and the title compound (102 mg (yield 84%)) was obtained as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=[O:4]
Reactant: COc1cccc(C(=O)CBr)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CBr)c1cccc(O)c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-bromo-1-(3-methoxy-phenyl)-ethanone (Aldrich, 3.44 g, 15 mmol) in methylene chloride (20 mL) at −10° C., boron tribromide (Aldrich, 16.5 mmol, 1M solution in CH2Cl2, 16.5 mL) was added slowly and the mixture was stirred for 1.5 hours. The reaction was quenched with ice water and the organic layer was separated. The aqueous layer was extracted with EtOAc and the extracts were combined and dried with sodium sulfate. Removal of solvent gave a greenish solid which was purified by chromatography (EtOAc/Hexane, 25%) gave an off-white solid. 770 mg, 24%. The compound was used directly for the next step.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][CH:28]=[C:17]([OH:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccc(O)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-hydroxy-DL-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in low yield.
Reaction SMILES: N#N.[C:3]1([CH3:11])[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:12][CH2:13][Mg+].[Br-].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC>[C:3]1([CH3:11])[CH:8]=[CH:7][C:6]([C:9]2([NH2:10])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CC[Mg+]
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Product: Cc1ccc(C2(N)CC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of p-tolunitrile (1195 mg, 10.00 mmol) in dry Et2O (50 mL) was treated at −78° C. with Ti(Oi-Pr)4 (3.22 mL, 11.00 mmol) followed by EtMgBr (7.33 mL of a 3.0 M solution in Et2O, 22.00 mmol). The resulting yellow suspension was stirred at −78° C. for 10 min, then warmed up to rt. To the resulting black suspension was added BF3.Et2O (2.47 mL, 20.00 mmol) and the reaction mixture was stirred at rt for 1 h. Aqueous 1N HCl (30 mL) was carefully added, followed by Et2O and then 10% aqueous NaOH (100 mL). The layers were separated and the aq. layer extracted with Et2O. The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC(CH2Cl2/MeOH/NH4OH, 1:0:0→90:10:0.5) to get the title amine as a yellow oil. TLC: rf (CH2Cl2/MeOH/NH4OH, 95:5:0.5)=0.46. LC-MS-conditions 07b: tR=0.49 min; [M+H]+=148.29.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:31])([F:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:25](OCC)=[O:26])=[C:18]([C:20](OCC)=[O:21])[N:19]=2)=[CH:11][CH:10]=1.S(=O)(=O)(O)O.O>C1COCC1.C(OCC)(=O)C.ClCCl>[OH:26][CH2:25][C:17]1[S:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:31])([F:30])[F:7])=[CH:14][CH:13]=2)=[N:19][C:18]=1[CH2:20][OH:21]
Reactant: CCOC(=O)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminum hydride (0.14 wt) in THF (3.4 vols), add a solution of the diethyl 2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4,5-dicarboxylate (1.0 wt, 1.0 eq), dissolved in THF (2 vols) at a rate such that the temperature of the reaction mixture is maintained at below −10° C. The addition time is 1.5–3.0 hr. After the addition is complete, stir the reaction mixture at ambient temperature for 18 h. Quench the reaction by adding aqueous 16% sulfuric acid (2.4 vols). Charge ethyl acetate (5 vols) with stirring to the reaction mixture followed with water (5 vols). Filter the resulting two phase mixture through celite (0.4 wt). Separate the layers and wash the organic layer with water (4×4 vols) and with brine (2×4 vol). Reduce the total volume of the reaction mixture via vacuum distillation to leave the solid suspended in ethyl acetate (1–1.5 vols). Dilute the slurry with dichloromethane (5 vols) and stir the suspension for at least 6 h. Filter the tan-colored solid. Wash the wet cake with dichloromethane (2 vols) and dry the wet cake at 45° C. under mild vacuum to afford the title compound as an off-white solid.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[F:6][C:7]([F:48])([F:47])[C:8]1[CH:9]=[C:10]([C@H:18]([N:20]([CH3:46])[C:21]([N:23]2[CH2:28][CH2:27][C@@H:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]3)[CH2:25][C@@H:24]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[CH3:45])=[O:22])[CH3:19])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1>C1COCC1>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[F:17][C:14]([F:15])([F:16])[C:12]1[CH:11]=[C:10]([C@H:18]([N:20]([CH3:46])[C:21]([N:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:37])[CH3:36])[CH2:33][CH2:34]3)[CH2:25][C@@H:24]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[CH3:45])=[O:22])[CH3:19])[CH:9]=[C:8]([C:7]([F:47])([F:6])[F:48])[CH:13]=1
Reactant: CC(=O)N1CCN([C@@H]2CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCN([C@H]2CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)CC1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
Sulfuric acid 96% was added (0.06 mL) to a solution of example 1 b (0.65 g) in THF (6.5 mL) at 23° C. under a nitrogen atmosphere. The suspension was stirred at 23° C. for 15 hours, then cooled to 4° C., stirred for 4 hours and allowed to warm to r.t. The solid was filtered off and dried at 23° C. for 18 hours to give the title compound (0.681 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[ClH:23]>CCOC(C)=O>[ClH:23].[ClH:23].[NH2:15][C:10]1([C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CN1CCN(C(=O)C2(NC(=O)OC(C)(C)C)CCCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)C2(N)CCCC2)CC1
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentylcarbamate (2.2 g, 7.06 mmol) in EtOAc (120 ml) at 4° C. was saturated with HCl gas, and the reaction then stirred for 4 h. The mixture was azeotroped with EtOAc, then dry Et2O, and dried under vacuum to afford (1-aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride (2.1 g) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH2:21][CH2:22][CH3:23])[N:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH2:21][CH2:22][CH3:23])[N:8]=1
Reactant: CCCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCc1nc(Cl)c(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (8.10 mL) was added to a mixture of dimethyl 2-hydroxy-6-propylpyridine-3,5-dicarboxylate (11 g) and acetonitrile (50 mL), and the resultant mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and then, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (11.8 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C
Yield: 87.7 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (375 mg, 0.95 mmol, prepared in example 2) and 4-cyanophenylboronic acid (168 mg, 1.14 mmol) were dissolved in 20 mL of n-propanol and 25 mg (0.18 mmol)of potassium carbonate in 5 mL of water added. A catalytic amount of palladium acetate is added (11 mg) and the mixture refluxed at 90° C. for 7 hours. The reaction is worked up as in preparation 6. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica chromatography using a Chromatotron® was achieved eluting with 99:1 methylene chloride:methanol to afford 307 mg (87%) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9](=[O:26])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]([OH:26])[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1OC
Solvent: CCO
Product: COc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2O)cc1OC

Procedure:
In a 1 L 3N round-bottomed hydrogenation flask, 7-acetoxy-3-(3,4-dimethoxyphenyl)-8-methylchromen-4-one (13.9 g) and Pd/Al2O3 (2.8 g) were suspended in absolute ethanol (560 mL). Hydrogen was introduced to the system for 42 h until the reaction was complete. The reaction mixture was separated by filtration with Celite. The solvent was removed in vacuo to give a white solid which was dried overnight on a high-vacuum line yielding 7-acetoxy3-(3,4-dimethoxyphenyl)-8-methylchroman-4-ol as a mixture of cis- and trans-isomers (9.56 g, 68%). This mixture was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O1CCCC1.[CH3:11][C:12](=O)[CH2:13][C:14](=[O:16])[CH3:15]>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:12]([CH3:11])=[CH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: COCCN
Solvent: O
Solvent: C1CCOC1
Product: COCCNC(C)=CC(C)=O
Reaction time: 8 h

Procedure:
7.50 g of 2-Methoxyethylamine (0.1 moles) were dissolved into 100 ml of tetrahydrofuran to which 10.0 g of 2,4-pentanedione (0.1 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH2OMe)Me=11.8 g (75% of theoretical).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Product: O=C(N[C@H]1CC[C@H](O)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation E) and (trans)-4-aminocyclohexanol to yield the title compound as a white solid (31 mg, 62% yield). MS (apci) m/z=424.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[F:14])[CH3:2].[Sn].Cl>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl
Agent: [Sn]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid ethyl ester (725 mg, 3.4 mmol) in tetrahydrofuran (11 ml) was treated with tin metal (807 mg, 6.8 mmol, 2 equiv.) and 6N HCl (5.4 ml). The mixture was warmed to 50° C. and stirred for 30 min. After cooling to room temperature, the solvent was evaporated. The residue was cooled to 0° C. and treated with 10% NaOH (20 ml). After stirring for a few minutes, the suspension was filtered, washing with water. The solid was dissolved in tetrahydrofuran and treated with Na2SO4. Filtration and evaporation of the solvent yielded a light yellow solid, which was purified by trituration in diisopropylether. 4-Amino-2-fluorobenzoic acid ethyl ester was obtained as a light yellow solid, 554 mg (89% yield), MS (ISP): m/e=184.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[BH3-]C#N.[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[NH:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:24]2[CH:33]3[CH:28]([CH2:29][CH2:30][CH2:31][CH:32]3[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:27]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccn2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine-2-carbaldehyde (268 mg, 2.5 mmol) was dissolved in MeOH (5 ml) and NaBH3CN (157 mg, 2.5 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (98 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted five times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified four times by flash chromatography (in each case Ø 2 cm, l=15 cm, V=5 ml; 1. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 2. CH2Cl2/MeOH/NH3 9.5:0.5:0.1, 3. CH2Cl2/MeOH/NH3 9.75:0.25:0.15, 4. CH2Cl2/MeOH/NH3 9.5:0.5:0.15). The crude product was then purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A yellowish resin was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([CH2:29][CH3:30])[C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[CH2:29]([NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)[CH3:30]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2ccc(C(=O)OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN[C@@H]1CCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
TFA (25 ml) was added dropwise at 0° C. to a solution of (R)-methyl 3-(tert-butoxycarbonyl-(ethyl)amino)-2,3-dihydro-1H-indene-5-carboxylate (10.84 g, 33.97 mmol, 1 eq) in DCM (100 ml), and the mixture was stirred for 1 hour at RT. After monitoring by TLC, the reaction solution was concentrated under reduced pressure, the residue was taken up in sat. sodium hydrogen carbonate solution (500 ml) and extraction with ethyl acetate (3×1000 ml) was carried out. The combined org. phases were washed with sat. sodium chloride solution (800 ml), dried over sodium sulfate, concentrated and used in the following stage without being purified further. The desired product was in the form of a light-brown liquid. Yield: 91% (6.8 g, 31.05 mmol)
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([C:18](=[O:32])[C@@H:19]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:20]([CH3:22])[CH3:21])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]([NH:23][C@@H:19]([CH:20]([CH3:22])[CH3:21])[C:18]([N:8]([CH2:7][C:6]([OH:33])=[O:5])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 723 (240 mg, 0.53 mmol) in CH2Cl2 (4.0 mL) was added TFA (2.0 mL) and the reaction stirred at rt for 1 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene. The material was used directly in the next reaction without further purification. ##STR103##