Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([OH:11])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Product: O=C(Cc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-phenylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 249, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-phenylacetamido)propanamide (3 mg, 50.1%). MS (EI) for C30H27FN2O4. found 499.6 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:20](=[O:38])[C:19]=3[C:18]=2[O:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.CO.[OH-].[Na+]>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:20](=[O:38])[C:19]=3[C:18]=2[O:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1ccccn1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1ccccn1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 2-[4-({[3-methoxy-1-methyl-4-oxo-5-(pyridin-2-ylmethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (60 mg) in THF (2 mL)-methanol (2 ml) was added 2N sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (25 mg, 45%) as beige crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7](S(C)(=O)=O)[N:6]=1)(=[O:4])=[O:3].[C-]#N.[K+].CN(C=[O:37])C>>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([OH:37])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)(=[O:4])=[O:3]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [C-]#N
Agent: [K+]
Product: CS(=O)(=O)c1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
To a round bottom flask fitted with a magnetic stir bar and rubber septum was added 2 mL DMF, 6-[2,4-dichlorophenyl]-5-[4-chlorophenyl]-2,4-bis(methylsulfonyl)pyrimidine (Reference Example 5) (98 mg, 0.2 mmol) and potassium cyanide (15 mg, 0.22 mmol). The mixture was heated for 30 min at 80°. By LC, all starting material was consumed (Rt=3.59 min) and a new peak appeared (Rt=3.50 min). The molecular weight corresponded not to the cyano derivative, but to 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. (HPLC/MS: m/e=430 (M+)) probably due to the fact that the solvent was not anhydrous.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:9](=[O:11])[CH3:10])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
The title compound is prepared by the procedure of Example 12 using 25 g of 4-(aminomethyl)pyridine, 25.1 ml of acetic anhydride, 2.26 g of 4-dimethylaminopyridine, 80 ml of pyridine and stirring at room temperature for 68 hours. The residue is purified by column chromatography (silica gel:20% methyl alcohol/ethyl acetate) to give 3.82 g of desired product as orange crystals.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7]([OH:9])=O)=[O:3].FC(F)(F)C(O)=O.N[C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49](F)[CH:48]=[C:47](F)[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1>>[CH2:44]([C@H:30]([NH:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
Following the procedure of CHART P and EXAMPLE 739 and making non-critical variations but using 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoic acid (IX) and (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanol (VIII), the title compound is obtained, HRMS (FAB)=615.3571.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=23)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of acryloyl chloride (42 μL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 141, 240 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (135 mg, 50%) as a yellow solid after trituration with CH3CN; 1H NMR: 1.61-1.74 (2H, m), 1.73-1.85 (2H, m), 1.87-1.99 (2H, m), 2.03 (2H, t), 2.35 (3H, s), 2.61 (2H, t), 3.01 (2H, t), 3.60 (2H, d), 3.84 (3H, s), 3.89 (2H, d), 4.09 (2H, t), 5.70 (1H, d), 6.14-6.30 (2H, m), 6.47 (1H, dd), 6.95 (1H, d), 7.73 (1H, s), 7.83 (1H, s), 8.05 (1H, s), 8.26 (1H, d), 9.26 (1H, s); m/z: ES+ MH+ 515.7.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[O:19]=[C:7]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:3]2[CH2:2][N:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:40][C:28](=[O:29])[C:4]=2[C@@H:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)[NH:6]1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: NNc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc([C@H]2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)NN(c2ccccc2)C3)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
80 mg (0.16 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(tri-fluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were dissolved in 2 ml of dioxane, 51 mg (0.47 mmol) of phenylhydrazine were added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was then concentrated, and the residue that remained was purified by preparative HPLC (Method 10). The product fractions were combined and concentrated, and the solid that remained was dried under reduced pressure (Yield: 24.0 mg, 31% of theory).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([S:24]([CH:27]1[CH2:30][NH:29][CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([S:24]([CH:27]1[CH2:30][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCS(=O)(=O)C1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.9 mL), 3-(pentylsulfonyl)azetidine hydrochloride (39 mg, 0.17 mmol; which may be prepared as described in Step 4), DIPEA (106 μL, 0.64 mmol), DMAP (2 mg, 0.02 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: 90/10 DCM/MeOH) then triturated in pentane with a drop of acetone to give the title compound (12 mg, 19%) as a white solid.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.O1CCCC1.N1(O[C:23](=[O:39])[CH2:24][C@H:25]2[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)C2C=CC=CC=2N=N1>C(OCC)(=O)C>[CH3:1][NH:2][C:23](=[O:39])[CH2:24][C@H:25]1[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)On2nnc3ccccc32)OC1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methylamine/tetrahydrofuran solution (2.0 mol/l, 1 ml) was added to a tetrahydrofuran (5 ml) solution of the compound (378 mg, 1.00 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [methanol:ethyl acetate=5:95 (v/v)] to give 135 mg (49%) of the title compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([CH3:3])[CH3:2].[F-:14].[K+].O>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([F:14])(=[O:12])=[O:11])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)c1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccccc1S(=O)(=O)F
Reaction time: 45 h
Yield: 96.1 %

Procedure:
27 g of 2-isopropylbenzenesulfonyl chloride and 22 g of KF are stirred in 75 ml of dioxane and 20 ml of water at 45° C. for 27 h and at RT for 45 h. 800 ml of water are then added, and the mixture is extracted with 3×300 ml of EA. The combined organic phases are dried over Na2SO4 and the solvent is removed in vacuo. 24 g of a colorless oil are obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([Cl:26])=[CH:23]3)=[CH:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[Cl:26][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][N:17]([S:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])[CH:18]=2)[CH:23]=1
Reactant: O=S(=O)(N1CCN(Cc2ccccc2)CC1)n1cc2ccc(Cl)cc2c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: O=S(=O)(N1CCNCC1)n1cc2ccc(Cl)cc2c1
Reaction time: 0.25 h

Procedure:
To a solution of 1-benzyl-4-[(5-chloroisoindol-2-yl)sulfonyl]piperazine (222 mg) in 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (81 mg) was added under ice cooling. The resulting mixture was stirred for 15 minutes and then heated under reflux for 1 hour. After cooling, anhydrous methanol was added to the residue obtained by distilling off the solvent under reduced pressure. The mixture was heated under reflux for 11 hours. After cooling, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethanol:dichloromethane=1:50 to 1:10), whereby the title compound (120 mg, 70%) was obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].C(O)CCC>[Pd].O>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: CCCCO
Solvent: O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.200 g), 50% wet 10% palladium on carbon (0.256 g), 1-butanol (20 ml) and water (20 ml) is hydrogenated in a Parr apparatus at 56 psi for 8 hours. The catalyst is then removed by filtration through diatomaceous earth and washed with 2×6 ml of water. The 1-butanol layer is extracted once with 6 ml of water. The combined aqueous solution (ca. 38 ml) is extracted twice with 2×10 ml of isopropyl acetate, concentrated under reduced pressure below 28° C. to ca. 20 ml and lyophilized to give 97.1 mg (83.0%) of the desired product as a slightly tan solid. MS (ES), m/z:442.3 (M+H)+; rotation [α]D25+42±1° (c 0.84, H2O); purity by analytical HPLC (100%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH3:28])[C:12]([CH2:15][O:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])=[N:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:8][C:9]1[C:10](=[O:29])[N:11]([CH3:28])[C:12]([CH2:15][O:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])=[N:13][CH:14]=1
Reactant: Cn1c(CON2C(=O)c3ccccc3C2=O)ncc(OCc2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(CON2C(=O)c3ccccc3C2=O)ncc(O)c1=O
Temperature: -70 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
N-[[5-(Benzyloxy)-3,4-dihydro-3-methyl-4-oxo-2-pyrimidinyl]methoxy]phthalimide (1.56 g) (4 mmol) are dissolved in 110 ml of dichloromethane and treated dropwise at about -70° C. while stirring with 0.42 ml (4.4 mmol) of boron tribromide. After stirring at about -70° C. for 4 hours and at room temperature for 16 hours the solvent is removed in a water-jet vacuum at room temperature. The residue is treated with about 30 ml of water, the insoluble product is filtered off and washed firstly with water and subsequently with diethyl ether. After drying in a high vacuum at room temperature for 18 hours there are obtained 1.1 g of N-[(3,4-dihydro-5-hydroxy-3-methyl-4-oxo-2-pyrimidinyl)methoxy]phthalimide as a white powder, m.p. 172° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[C:30]([F:37])[N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([C:23]([F:25])([F:26])[F:24])[CH:3]=2)[CH:31]=[C:30]([F:37])[N:29]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cc(F)nc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 42.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2,6-difluoropyridine-4-boronic acid (0.063 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.055 g) to obtain the title compound (0.055 g) as a brownish solid. MS (ISP): 520.2 (M+NH4)+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[S:9][C:10]([CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=O)=[C:11](CCCC2C=CC(C)=CC=2)[C:12]=1C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)Cl.CCOCC>[O:36]1[CH2:37][CH2:38][N:33]([C:28]([CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][CH2:24][C:10]2[S:9][CH:8]=[CH:12][CH:11]=2)=[O:30])[CH2:34][CH2:35]1
Reactant: C1COCCN1
Reactant: Cc1ccc(CCCc2c(CCC(C)(C)CC(=O)O)sc(C)c2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)(CCc1cccs1)CC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
2 g (0.0157 mol) of oxalyl chloride dissolved in 10 ml of CHCl3 are placed in a 100 ml single-necked flask. After having brought the mixture to 0° C. with an ice bath, 3.9 g (0.0105 mol) of 2,3-dimethyl-4-(3-p-methylphenylpropyl)-5-(4-carboxy-3,3-dimethylbutyl)thiophene (see above, paragraph B of the synthesis of the starting materials) are added. The reaction mixture is then stirred at room temperature and subsequently at 50° C. until the evolution of gas has ceased. The solvent is distilled off at a temperature below 50° C. The acid chloride prepared above dissolved in 60 ml of ether, and 1.82 g (0.021 mol) of morpholine dissolved in 60 ml of ether, are simultaneously poured into a 500 ml three-necked flask while stirring. The morpholinium hydrochloride precipitates instantaneously. After one hour's stirring, the solid is removed by filtration. The filtrate is washed with water, dried over MgSO4, rendered colourless with carbon black and concentrated to dryness. The crude product obtained is purified by chromatography on silica (eluant: CH2Cl2 /CH3COOC2H5 -95/5, then CH2Cl2 /CH3OH-98/2). 3.31 g of 2,3-dimethyl-4-3-p-methylphenylpropyl)-5-(4-morpholinocarbonyl-3,3-dimethylbutyl)thiophene are obtained in the form of a colourless oil, yield: 72%.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:36])[N:4]2[C:29](=[CH:30][C:31]=1[C:32](=[O:35])[CH2:33][CH3:34])[C:7]1=[N:8][C:9]3[C:14]([C:15]([CH2:16][O:17][C:18](=[O:28])[CH2:19][NH:20]C(OC(C)(C)C)=O)=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(C(O)=O)(F)(F)F.O>>[NH2:20][CH2:19][C:18]([O:17][CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[C:29]3[N:4]([CH2:5][C:6]=12)[C:3](=[O:36])[C:2]([CH3:1])=[C:31]([C:32](=[O:35])[CH2:33][CH3:34])[CH:30]=3)=[O:28]
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1COC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(=O)c1cc2n(c(=O)c1C)Cc1c-2nc2ccccc2c1COC(=O)CN

Procedure:
The title compound was prepared according to the procedure in Example 5B except using 8-methyl-12-[[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (D2O/DSS) d 7.6-7.3 (m, 4H), 6.64 (s, 1H), 5.58 (s, 2H), 4.58 (s, 2H), 4.20 (s, 2H), 2.92 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Anal. Calcd for C22H21N3O4.CF3CO2H.H2O: C, 55.07; H, 4.62; N, 8.03. Found: C, 55.32; H, 4.69; N, 7.98.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 4-(chloromethyl)anisole (1.95 g) was allowed to stand overnight at ambient temperature, under nitrogen, with stirring. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 7.5% acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.5 g (40%) of product, mp 39-40° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16].O>ClCCl>[CH:1]([NH:14][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzhydrylamine (1.83 g) was dissolved in dichloromethane (3.0 ml). Carbonyldiimidazole (1.78 g) was added to the solution. The mixture was stirred at room temperature overnight. Water and dichloromethane were added thereto. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation is to give imidazole-1-carboxylic acid benzhydrylamide.