Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I.C([O-])(=O)C.[Na+].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(OC)(C)(C)C>[CH2:28]([O:27][C:23](=[O:26])[CH:24]=[CH:25][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1])[CH3:29]
Reactant: C=CC(=O)OCC
Reactant: Fc1ccc(Br)c(OCc2ccccc2I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccccc1COc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a mixture of 1-bromo-4-fluoro-2-(2-iodo-benzyloxy)-benzene (117.4 g, 0.29 mol), sodium acetate (36.1 g, 0.44 mol), tetra-n-butylammonium bromide (90.3 g, 0.29 mol), palladium (II) acetate (1.8 g, 8 mmol, 3 mol %), and N-methylpyrrolidinone (900 mL) at 55-60° C., add dropwise a solution of ethyl acrylate (34.3 mL, 0.32 mol) in N-methylpyrrolidinone (200 mL). Cool the reaction mixture to room temperature and treat with water (2 L) and methyl tert-butyl ether (2 L). Pass the reaction through diatomaceous earth, add ethyl acetate (1 L), separate the layers, and wash with water (2 L). Dry the organic portion over anhydrous sodium sulfate, filter, and concentrate. Suspend the resulting solid in hexanes (1 L), refrigerate for 2 h, filter, and wash with cold hexanes (500 mL). Dry in a vacuum oven (50° C./20 mm Hg) to obtain the title compound as a pale yellow solid (104.4 g, 95%). LC-MS m/z 381.0 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][NH:7]1)=[O:5])C.[OH-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>CO.O1CCCC1.O.C(OCC)(=O)C>[CH2:49]([O:48][C:46]([N:7]1[CH2:8][C@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11][C@H:6]1[C:4]([OH:3])=[O:5])=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-2-carboxylic acid ethyl ester (from example 2) in 60 ml of methanol-tetrahydrofuran-water 1:1:1 are added 2.85 ml of a solution of 1N lithiumhydroxide at 0° C. Stirring is continued for an additional 2 hours at room temperature, followed by addition of 40 ml of ethyl acetate, 20 ml of saturated aqueous sodium carbonate solution and 0.42 ml of benzyl chloroformate. The reaction mixture is stirred for 1 hour, diluted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.13 (EtOAc); Rt=4.77.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.OOS([O-])=O.[K+].[CH3:24][OH:25]>>[CH3:24][O:25][C:9](=[O:10])[C:8]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:7]=1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 57.5 °C
Yield: 52 %

Procedure:
873 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (3.61 mol) were dissolved in MeOH (4.4 L), then solid Oxone® (1.86 Kg, 6.06 mol) was added portion-wise in 1 hour, and the solution was stirred and warmed to 55 to 60° C. for 2 hours. The solvent was concentrated under vacuum to 1.6 L and water (7 L) was added. The resulting heterogeneous solution was stirred at 50 to 55° C., then toluene (3 L) was added, and the biphasic mixture vigorously stirred. Aqueous phase was discharged and the organic one was washed with water (3 L). The solvent was concentrated under vacuum to 2 to 3 volumes, and the obtained solution warmed to 80 to 90° C. n-Heptane (5.5 L) was slowly added. The mixture was cooled to −10° C., and the suspension was stirred at −10° C. over-night. The solid was filtered on a Buchner funnel and washed with n-heptane (1 L). The obtained yellow solid was dried under vacuum at room temperature. (yield 52%).
Reaction SMILES: [CH3:1][N:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1>CCO.[Pd]>[CH3:1][N:2]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1N

Procedure:
A solution of methyl(2-nitrophenyl)(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtalen-2-yl)amine (12) (R4=CH3, 0.26 mol) in EtOH (3200 mL) is treated with 10% Pd/C (8.9 g) under hydrogen atmosphere at room temperature for 2.5 h. After filtration of the catalyst, the filtrate is evaporated to give the above diamine (13) (R4=CH3).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([O:5][NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N+:17]([O-])=O)=[O:4]>[Pd].C(O)C>[NH2:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][C@@H:7]([C:20]([OH:22])=[O:21])[NH:6][O:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:1])[CH3:23]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(F)c1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(F)c1N)C(=O)O
Yield: 92.5 %

Procedure:
790 mg of 48 (2.192 mmol), 79 mg of Pd/C (10%) and 20 mL of ethanol are hydrogenated at 7 bar for 10 hours at 20° C. in an autoclave. After filtering off the catalyst through Celite, the solvent is evaporated off and 670 mg of expected product 49 are obtained (yellow oil), which product is used directly in the following step.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)cc(OC)c1OC
Reactant: CN1CCNCC1
Product: COc1cc(-c2nc3ccc(OCCN4CCN(C)CC4)cc3n2Cc2ccccc2)cc(OC)c1OC

Procedure:
The title compound was prepared essentially as described in Example 77, supra, employing the compound of Example 76, except that 1-methylpiperazine was employed in place of the 4-(piperdin-1-yl)piperidine. IR, NMR, MS 517, mp 113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].ClC1C(N)=CC=CN=1.NC1C=C(C)C=CC=1C(OC)=O.S(=O)(=O)(O)O>S1(CCCC1)(=O)=O.ClCCl.C1(C)C=CC=CC=1>[CH3:18][C:16]1[CH:15]=[CH:14][C:3]2[C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[NH:1][C:2]=2[CH:17]=1
Reactant: Cc1ccc(C(=O)Nc2cccnc2Cl)c(N)c1
Agent: COC(=O)c1ccc(C)cc1N
Agent: Nc1cccnc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)Nc1ncccc1NC2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
127.0 g (0.485 mol) of 2-amino-N-(2-chloro-pyridin-3-yl)-4-methyl-benzamide (m.p. 150°-152° C.) prepared analogously to Example A from 2-chloro-3-amino-pyridine and methyl 2-amino-4-methyl-benzoate (see F. Mayer and R. Schulze, Ber. Dtsch. Chem. Ges. 58, 1465 [1925]) were suspended in 500 ml of sulpholane and after the addition of 1.4 ml of conc. sulphuric acid the suspension was heated for 3 hours to 130° C. with stirring. It was then left to cool to 80° C., 500 ml of toluene were added and the mixture was left to stand overnight at ambient temperature. The crystals formed were suction filtered, suspended in 0.75 liters of dichloromethane, suction filtered once more and thoroughly washed with dichloromethane. After drying in a circulating air dryer, 70.2 g (64% of theory) of very slightly yellow crystals were obtained, m.p. 286°-288° C., which were further reacted without any further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:30][NH:29][CH2:28]2)=[C:22]([CH3:31])[CH:21]=1>O1CCCC1>[F:12][C:9]1[CH:10]=[N:11][C:2]([N:29]2[CH2:30][CH:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=3[CH3:31])[CH2:28]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1cc(F)ccc1NC1CNC1
Reactant: COC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cnc1N1CC(Nc2ccc(F)cc2C)C1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 2-chloro-5-fluoronicotinate (D69) (199.85 mg, 1.054 mmol) and potassium carbonate (291 mg, 2.108 mmol) in tetrahydrofuran (2 ml) was stirred under N2 nitrogen 15 min at room temperature. N-(4-fluoro-2-methylphenyl)azetidin-3-amine (D55) (190 mg, 1.054 mmol) was added and the resulting mixture was stirred 1 day at room temperature. The residue obtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D90)(155 mg)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:25])=[N:17][C:18]([CH:22]5[CH2:24][CH2:23]5)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1.[OH-].[Na+].[F:34][C:35](F)([F:39])C(O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([CH:22]5[CH2:23][CH2:24]5)=[N:17][C:16]=4[CH3:25])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:26]([O:31][CH:35]([F:39])[F:34])[C:27]([F:29])([F:28])[F:30])=[CH:4][CH:3]=1
Reactant: Cc1nc(C2CC2)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Reactant: O=C(O)C(F)(F)F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(C2CC2)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[9-chloro-1-(2-cyclopropyl-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (305 mg, 0.675 mmol), benzyltriethylammonium chloride (7.7 mg, 0.0338 mmol), and 8N sodium hydroxide (2.7 mL) in tetrahydrofuran (2.7 mL) was stirred at room temperature under chloro(difluoro)methane atmosphere for 60 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 60-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (98.2 mg, 0.196 mmol, 29%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[CH:15]=[C:16]([C:20](=O)[CH3:21])[C:17]([NH2:19])=[O:18]>C(O)(C)C>[C:17]([C:16]1[CH:15]([C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[Cl:12])[N:3]2[CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=[C:2]2[NH:1][C:20]=1[CH3:21])(=[O:18])[NH2:19]
Reactant: COC(=O)Cc1c[nH]c(N)n1
Reactant: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Solvent: CC(C)O
Product: COC(=O)Cc1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of methyl 2-(2-amino-1H-imidazol-4-yl)acetate (986 mg, 6.4 mmol) and 2-(2,4-dichlorobenzylidene)-3-oxobutanamide (Example 158, Step 2, 1.64 g, 6.4 mmol) in isopropyl alcohol (40 mL) was placed as a slurry in a 100° C. oil bath. The mixture became a clear solution within 2 min and a precipitate formed during heating for 14.5 h. Upon cooling to room temperature, the tan solids were isolated by filtration with hexanes wash (2×15 mL) to provide methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidin-2-yl)acetate (1.14 g, 45%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]1([N:30]2[C:34]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[CH:33][C:32]([CH:40]=O)=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:40][C:32]3[CH:33]=[C:34]([C:35]4[O:36][CH:37]=[CH:38][CH:39]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: Clc1ccc(C(c2ccccc2)N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 62 %

Procedure:
Compound 97 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([C:13]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=O)=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[C:16]2=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]2[N:14]=1)[CH3:12].[OH-].[Na+].C(O)(=O)/C=C/C(O)=O>C1COCC1>[CH2:11]([C:13]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[C:16]2=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]2[N:14]=1)[CH3:12]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(Nc2ccc(C(=O)N3CCN(C)CC3)cc2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(Nc2ccc(CN3CCN(C)CC3)cc2)cc1
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
Lithium aluminum hydride (0.044 g, 1.16 mmol) was suspended in THF (5.0 mL), and a solution of aluminum chloride (0.0773 g, 0.580 mmol) in THF (7.0 mL) was added to the suspention at 0° C., followed by stirring at same temperature for 10 minutes. Then, a solution of Compound 100 (0.140 g, 0.290 mmol) in THF (6.0 mL) was slowly added to the mixture, followed by stirring at 0° C. for 15 minutes. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF, and a solution of fumaric acid (74 mg, 0.58 mmol) in THF (2 mL) was added to the solution. The precipitates were collected by filtration, and sequentially washed with THF and ethyl acetate to obtain Compound 102 (0.173 g, 0.247 mmol, yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C1C=CC2C=[C:25]([NH2:30])C=CC=2C=1.Cl.CN(C)CCCC(N=C=N)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH:30][CH3:25])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc2ccccc2c1
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before addition of napthylamine (40% solution in water, 0.11 μl, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 hours, solvent removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to yield the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: BrBr
Reactant: c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.94 ml (134.8 mmol) of bromine in 25 ml of acetic acid is slowly added dropwise over a period of 40 min to a solution of 20 g (122.5 mmol) of N-phenylmorpholine in 170 ml of acetic acid at room temperature. After stirring at room temperature for 30 min, the reaction mixture is stirred into 750 ml of water and adjusted to pH 11 with 45% strength sodium hydroxide solution. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. Recrystallization from ethanol results in 18.6 g (62.9% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)=[C:22]([CH2:31][CH2:32][CH3:33])[C:21]=1[OH:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:35])=[C:21]([OH:34])[C:22]=2[CH2:31][CH2:32][CH3:33])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(=O)OC)c1O
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(=O)OC)c1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.47 g) and 55% sodium hydride (0.116 g) in dimethylformamide (10 mL) was stirred for 15 minutes and then treated with 4-(3-bromopropoxy)-2-hydroxy-3-propylbenzoic acid methyl ester (0.8 g) in dimethylforrnamide (5 mL). The mixture was heated at 50° C. for 20 hours and worked up as in Example 20. The residual oil was purified by flash chromatography over silica gel (ethyl acetate-hexane; 3:17) and then was crystallized from hexane to give 0.6 g of 4-[3-[3-hydroxy-4-(methoxycarbonyl)-2-propylphenoxy) propoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 62°-64° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19](O)=[O:20])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:31][N:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:20])[NH:36][CH:34]2[CH2:35][N:32]([CH3:31])[CH2:33]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: CN1CC(N)C1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Agent: Cl
Product: CN1CC(NC(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and 1-methylazetidin-3-amine dihydrochloride (16 mg, 100 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (11 mg, 31%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C([O-])([O-])=O.[Na+].[Na+].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:17]=1[C:18](O)=[O:19])([O-:15])=[O:14]>[N+](C1C=CC=C([N+]([O-])=O)C=1C(Cl)=O)([O-])=O>[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:17]=1[C:18]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:19])([O-:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O

Procedure:
The reaction of 2,6-dinitrobenzoyl chloride (prepared from 2,6-dinitrobenzoic acid, 1 g and SOCl2, 10 mL) with L-alanine (0.52 g, 5.895 mmol) in the presence of Na2CO3 (0.625 g, 5.895 mmol) as described in intermediate 2 gave the title compound as a pale brown color solid (1.06 g, 80%), mp 222-224° C. 1H NMR (400 MHz, DMSO-d6): δ 12.81 (1H, br s), 9.23 (1H, d, J=7.6 Hz), 8.45 (2H, d, J=8.4 Hz), 7.92 (1H, t, J=8.2 Hz), 4.47 (1H, pentet, J=7.2 Hz), 1.33 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 282 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=2[CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: Cc1cccc(NCc2ncc[nH]2)c1C
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2cccc(C)c2C)[C@@H]1O
Yield: 36.9 %

Procedure:
The title compound (253 mg, 37%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 2,3-dimethylphenyl-1H-imidazol-2-ylmethylamine (287 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.