Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH:15]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)[CH3:17])([O:13][CH3:14])=[O:12]>>[C:11]([CH:15]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:26])=[CH:20][CH:19]=1)[CH3:17])([O:13][CH3:14])=[O:12]
Reactant: Cc1nc(C(O)CN)cs1
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using toluene/methanol =19:1 as eluant.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][CH:15]([O:24][CH2:25][CH3:26])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:17]([C:16]([CH:15]([O:14][CH2:12][CH3:13])[O:24][CH2:25][CH3:26])=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(OCC)OCC
Yield: 113.7 %

Procedure:
A solution of 3-nitrobenzaldehyde (2.27 g), ethyl 4,4-diethoxyacetoacetate (3.28 g) and piperidine (0.2 ml) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed three times with water and dried over magnesium sulfate. The solvent was removed from the reaction solution to give oily ethyl 2-(3-nitrobenzylidene)-4,4-diethoxyacetoacetate (6.0 g). The mixture of the compound obtained above and ethyl 3-aminocrotonate (1.94 g) was heated at about 95° to 100° C. for 7 hours and then at about 120° C. for 1.5 hours with stirring. After cooling, the resultant oil was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was removed from the resultant solution to give an oil (7.8 g). The product was purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate=20:1) to give the pure product of diethyl 2-methyl-4-(3-nitrophenyl)- 6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.65 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][C:26]=1[C:34](=[O:36])[CH3:35]>C(Cl)Cl.O1CCOCC1>[C:34]([C:26]1[C:25]([NH:24][C:8]([C:5]2[S:6][CH2:7][CH:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:30]([CH3:31])[C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:36])[CH3:35]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)C2=NC(C(F)(F)F)CS2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid (3.5 g, 1 eq.) in DCM (35 mL) at 0° C. under nitrogen was added anhydrous DMF (few drops) and oxalyl chloride (3.14 mL, 2 eq.). At the end of the gas evolution, the reaction mixture was allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hrs and was evaporated. Dioxane (70 mL) was added under nitrogen followed by a solution of 1-(2-amino-4-methoxy-3-methyl-phenyl)-ethanone 9 (3.18 g, 1 eq.) in dioxane (15 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was washed with saturated NaHCO3. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was triturated in Et2O to yield compound 202b as a white solid in 86% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.15 (s, 3H), 2.58 (s, 3H), 3.94 (s, 3H), 6.82 (d, J=8.55 Hz, 1H), 7.78 (d, J=8.55 Hz, 1H), 8.01 (s, 1H), 11.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:39])[CH:24]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:23]([NH:21][NH:22][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccccc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl (2-hydrazinyl-2-oxo-1-phenylethyl)carbamate 249 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 250 (0.40 g, 84%) as a white foam.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][O:8]C(=O)C)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:19]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:5][OH:4])[CH2:7][OH:8])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(=O)CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC(CO)(CO)NCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,3-Diacetoxy-2-octadecyl-2-(N-pentanoylamino)propane (400 mg) was dissolved in 30 ml of dry ether and 150 mg of lithium aluminum hydride was added thereto under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and 20 ml of dry tetrahydrofuran was added thereto. Under ice-cooling, 0.15 ml of water, 0.15 ml of a 15% aqueous sodium hydroxide solution and 0.45 ml of water were added-in order and the reaction mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography using chloroform-methanol-acetic acid (19:1:0.1→10:1:0.05) as an eluent to give 153 mg of colorless, powdery 2-octadecyl-2-(N-pentylamino)-1,3-propanediol.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5](O)=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:11][CH2:10]1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([C:5]([Cl:15])=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:11][CH2:10]1
Reactant: CC1(C)[C@@H](C=C2CC2)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)[C@@H](C=C2CC2)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 gm of dl-trans 3,3-dimethyl-2-cyclopropylidenemethyl-1-cyclopropanecarboxylic acid were introduced into 5 cc of benzene and 0.55 cc of thionyl chloride were added over about 15 minutes. Next, the reaction mixture was agitated for 3 hours at room temperature, after which the solvent and the excess thionyl chloride were eliminated by distillation under reduced pressure to obtain 1.2 gm of raw dl-trans 3,3-dimethyl-2-cyclopropylidenemethyl-1-cyclopropanecarboxylic acid chloride. The product was utilized as such for the next step.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(2-Hydroxy-3-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-3-methylbenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.63 (m, 4H), 3.71 (s, 2H), 5.39 (s, 1H), 6.69-6.73 (m, 1H), 6.82-6.83 (m, 1H), 7.05-7.07 (m, 1H), 7.84 (s, 1H), 10.60 (br s, 1H), 12.60 (br s, 1H). Mass spectrum (ES) MH+=301.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH:18]C(OC(C)(C)C)=O)([CH3:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH2:18])([CH3:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 84.6 %

Procedure:
To 74 g (149 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-carbo-t-butoxyamino-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 2) was added 74 g of trifluoroacetic acid and 74 g of chloroform. The mixture was refluxed for 40 minutes while gas was evolved and then an additional 20 minutes. The mixture was then concentrated in vacuo and then partitioned between ethyl ether and dilute aqueous sodium hydroxide. The organic layer was washed with brine, dried over magnesium sulfate, concentrated in vacuo, and the resulting solid was triturated with hexanes and filtered yielding 50 g (85%) of a white solid, mp 165°-167° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1>[CH3:27][C:26]([NH:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])=[CH:2][CH:1]=1)=[O:28]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC(Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
600 mg of melphalan (63) is suspended in 25 ml of water containing 500 mg of sodium carbonate. 10 ml of dioxane is added and 1 ml of acetic anhydride. After stirring at ambient temperature for 1 h citric acid is added and the mixture extracted with ethyl acetate. After washing with water and brine the organic phase is dried (sodium sulfate) and concentrated in vacuum. Removal of all volatiles yields the crude N-acetylmelphalan that is carried on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:30]([O:34][C:35](=[O:46])[NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH2:45])[CH:39]=1)([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCOC(C)=O>[C:30]([O:34][C:35](=[O:46])[NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH:45][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (0.195 g, 0.89 mmol) in THF (5 mL) is added carbonyl diimidazole (0.18 g, 1.1 mmol) and heated at 60° C. for 2 hours. The mixture is cooled to room temperature. (3-Aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.25 mL, 1.1 mmol) is added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with brine (2×50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford [3-({[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.32 g, 80%) as a solid. MS: 451 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.65 (s, 3H), 4.14 (d, J=6.1 Hz, 2H), 4.50 (d, J=5.6 Hz, 2H), 7.15 (m, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 8.13 (m, 1H), 8.28 (m, 1H), 8.89 (s, 1H), 9.23 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)C=O)[CH3:2].[C:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1)#[N:16].N1CCCC1.[CH:34]([OH:37])(C)C>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]2[C:7]([C:15](=[NH:16])[CH:17]([C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)[C:34](=[O:37])[O:12]2)=[CH:10][CH:11]=1)[CH3:14]
Reactant: CC(C)O
Reactant: N#CCc1nc(-c2ccccc2)cs1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: C1CCNC1
Product: CCN(CC)c1ccc2c(c1)OC(=O)C(c1nc(-c3ccccc3)cs1)C2=N
Yield: 81.3 %

Procedure:
3.9 parts of 4-diethylaminosalicylaldehyde and 4 parts of 2-cyanomethyl-4-phenyl-thiazole in 40 parts by volume of isopropyl alcohol are refluxed with 0.5 part by volume of pyrrolidine for 1 hour. The reaction mixture is then cooled and the precipitate is filtered off and washed. 6.1 parts (81.3% of theory) of 7-diethylamino-3-(4-phenylthiazol-2-yl)-iminocoumarin, of melting point120°-128° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:3]([C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3)c2)cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCC3CCCN3Cc3ccccc3)c2)cnc1N
Reaction time: 1 h
Yield: 225 %

Procedure:
To a stirred solution of 3-amino-N-methyl-6-(3-{[(pyrrolidin-2-ylmethyl)amino]carbonyl}phenyl)pyrazine-2-carboxamide (35.4 mg, 0.01 mmol) and benzaldehyde (24.8 mg, 0.02 mmol) in methanol (3 mL) was added sodium cyanoborohydride (25 mg, 0.04 mmol). The mixture was stirred for 1 h and then acetic acid added until the pH of the solution was 7.0. The solution was stirred for an additional 6 h, solvent was removed and residue was partitioned with CHCl3 and 2 M aqueous sodium hydroxide (5 mL). The aqueous phase was extracted with additional CHCl3 (2×5 mL) and the combined organic layer were washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography provided 10 mg of 3-amino-N-methyl-6-{3-[({[1-(phenylmethyl)pyrrolidin-2-yl]methyl}amino)carbonyl]phenyl}pyrazine-2-carboxamide: 1H NMR (400 MHz; CDCl3); 8.7 (s, 1H); 8.65 (s, 1H); 8.28 (br s, 1H); 7.95 (d, 1H); 7.22 (d, 1H); 7.53 (t, 1H); 7.2-7.4 (m, 5H); 4.3-3.5 (m, 7H); 2.95 (d, 3H); 2.35-1.8 (m, 4H); MS (EI) for C25H28N6O2: 445 )
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[CH:25]([C:27]([CH3:29])=[O:28])=[CH2:26].[OH-].[K+].Cl>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH:12]=3)[CH2:26][CH2:25][C:27](=[O:28])[CH:29]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: COc1ccc(C(C=O)c2ccc(Br)cc2)cc1OC1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(c3ccc(Br)cc3)C=CC(=O)CC2)cc1OC1CCCC1
Temperature: -10 °C

Procedure:
To a solution of 2-(4-bromophenyl)-2-(3-cyclopentyloxy-4-methoxyphenyl) acetaldehyde (2.60 g, 6.7 mmol) in THF (10 ml) was added methyl vinyl ketone (670 ul, 8.4 mmol). The solution was stirred at −10° C. and 10% ethanolic potassium hydroxide (480 ul) was added slowly. After 0.5 h the reaction mixture was warmed to room temperature and stirred for additional 1 h. Water and ethyl acetate were added and the mixture was neutralized with 3N hydrochloric acid. The layers were separated and the aqueous layer washed twice with ethyl acetate. The combined organic extract was washed with water then brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (silica gel, 12% ethyl acetate/82% hexane) provided the title compound as a pale white waxy solid (1.39 g, 47%). MS (m/e): 441 [(M+1)+], 443 [(M+3)+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[C:8]([C:11]3[S:12][C:13]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[CH:9]=[CH:10][C:2]1=2.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][C:42](=O)[O:43]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][C:42]([N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[S:12][C:13]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)=[CH:7][C:3]1=2)=[O:43]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)NCCO3)sc1N(C)CCOc1ccccc1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)sc1N(C)CCOc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 310.1 %

Procedure:
To ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20B) (0.150 g, 0.34 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (0.349 g, 0.11 mmol) was added acetonitrile (10 mL). The reaction mixture was allowed to heat to 85° C. and stirred for 8 hours. Then the reaction mixture was allowed to heat at 70° C. and stirred overnight. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. To the concentrate was added EtOAc and water and filtered. The layers of the filtrate were separated and extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.21 g (quantitative) ethyl 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20C): LC/MS (APCI): m/z 616.3 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Product: O=c1[nH]c2cccc(OCC(O)CNC3CCN(c4ccc(S(=O)(=O)NCc5ccccc5)cc4)CC3)c2[nH]1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a grey solid. 1H NMR (DMSO) δ 1.37 (m, 2H), 1.90 (m, 2H), 2.73 (m, 2H), 2.84(m, 2H), 2.99(m, 4H), 3.87(m, 3H), 4.03(m, 1H), 5.07(bs, 1H), 6.67 (m, 1H), 6.85(t, 1H, J=8.1 Hz), 7.07(d, 2H), J=9.0 Hz), 7.32 (m, 6H), 7.59 (d, 2H, J=8.7 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 552.1 (MH+); HRMS for C28H33N5O5S: 552.2267 (MH+).
Reaction SMILES: [Na].[CH3:2][C:3](=O)[CH2:4][CH2:5][C:6](=O)[CH3:7].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.O>CO.C(OCC)C>[CH3:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[C:10]2[C:11]=1[CH:12]=[CH:13][CH2:14]2
Reactant: C1=CCC=C1
Reactant: CC(=O)CCC(C)=O
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C=CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23 g (1.0 mol) of sodium were dissolved in 250 ml of absolute methanol. A mixture of 45.6 g (0.40 mol) of 2,5-hexanedione and 39.7 g (0.60 mol) of cyclopentadiene was added dropwise at 0° C. in the course of 1-2 hours. After stirring at room temperature for 1 hour, 50 ml of H2O were added to the dark brown solution. The organic phase was diluted with about 1 l of diethyl ether. The aqueous phase was separated off. The organic phase was dried over sodium sulfate and evaporated. The oil which remained was chromatographed on silica gel 60. 44.2 g (76%) of the indene 1 could be eluted with hexane/methylene chloride (10:1), and is obtained as a colorless to pale yellow oil after the mobile phase has been stripped off under an oil pump vacuum. For the NMR data, see Table 1.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-methylbenzaldehyde. MS (ESI) m/z 483.