Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C:4](=O)[CH2:3]1.C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][CH:4]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=2)[CH2:3]1
Reactant: [H][H]
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: COc1ccc(N)cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1
Reaction time: 7 h

Procedure:
A solution of 35.6 g of 6-methyl-8-oxo-ergoline in 1.4 liters of glacial acetic acid is slowly added dropwise to 35 g of 10% palladium on active charcoal and 18.6 g of 2-methoxy-5-aminopyridine in 400 cc of glacial acetic acid with simultaneous hydrogenation under normal conditions. The addition is effected within about 7 hours. After the hydrogen take up is complete, the catalyst is filtered off, the filtrate is concentrated in a vacuum and the resulting residue is taken up in methylene chloride (+15% of isopropanol) and washed with ice-cooled ammonia and water. The residue obtained after drying the combined organic phases and concentrating by evaporation, is purified and separated into the isomers by chromatography on an 80-fold quantity of silica gel with methylene chloride and the addition of increasing amounts of methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1.C(OCC)C>O1CCCC1.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]5[CH2:23][N:24]([CH3:26])[CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:38])=[CH:34][CH:35]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 48 %

Procedure:
To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (100 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 2.61 ml) at room temperature, followed by stirring at room temperature for 4.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether was added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (70.4 mg, 48.0%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])=[O:31])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.71 g, 5 mmol) in CH2Cl2 (60 mL) was added m-CPBA (1.17 g, 5.2 mmol). The mixture was stirred at room temperature for 10 minutes, then directly loaded onto a column. Flash chromatography (mobile phase EtOAc/Hexane) afforded the title compound as a white solid 1.58 g (88%). LC-MS m/z 358 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6]>C(Cl)(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6]
Reactant: Cc1ccc(CO)cc1Br
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C=O)cc1Br
Temperature: 70 °C
Yield: 68.5 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzyl alcohol (4.43 g, 22 mMol) in CHCl3 (100 mL) was added MnO2 (15 g, 172 mMol). The reaction was stirred and refluxed (70° C. oil bath) for 18 h, cooled to RT, filtered through Celite®, rinsed with CHCl3, and concentrated to dryness under vacuum. Purification by flash chromatography on silica gel (10% EtOAc, hexanes) gave the title product (3.0 g, 68%). 1H NMR (400 MHz, CDCl3) δ9.98 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57 (dd, J=8.1, 1.5 Hz, 1H), 7.28 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19]Br.CCOC(C)=O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: BrCCCn1c2ccccc2c2ccccc21
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 9H-carbazole (5 g, 29.94 mmol, 1.00 equiv) in THF (200 mL). To this was added NaH (1.8 g, 75.00 mmol, 1.50 equiv) in small portions at and allowed to stir for 30 minutes. To the mixture was added 1,3-dibromopropane (18 g, 89.55 mmol, 3.00 equiv) at −10° C. and warmed up to 30° C. in an oil bath for 30 minutes. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). Combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate. Solids were filtered off and the mixture was concentrated on a rotary evaporator affording 9-(3-bromopropyl)-9H-carbazole as yellow solid (10 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.C[N:18]([CH:20]=[O:21])C.[C:22]1([C:28]2[CH:36]=[CH:35][C:31](C(Cl)=O)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[C:22]([C:28]3[CH:36]=[CH:35][CH:31]=[CH:30][CH:29]=3)[CH:23]=[CH:24][C:25]=2[C:20]([NH2:18])=[O:21])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(O)ccc1-c1cc(-c2ccccc2)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
4-Amino-3-methylphenol (270 mg, 2.20 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 1.0 ml of dry DMF. Next, 0.3 ml (1 eq.) of dry triethylamine was added. Next, a dry DMF solution (3.0 ml) of 4-phenylbenzoyl chloride (478 mg) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 100 ml of cold water, suction filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column chromatography (silica gel eluted with methylene chloride) to obtain 648 mg of the intended product, 4-hydroxy-2-methylphenyl-4-phenylbenzamide (yield: 96%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15](OC(C)(C)C)=O>>[F:22][C:14]([F:23])([C:15]1[O:11][N:10]=[C:8]([NH2:9])[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]([F:25])([F:24])[F:12]
Reactant: CC(C)(C)OC(=O)C(F)(F)C(F)(F)F
Reactant: NC(Cc1ccccc1)=NO
Product: Nc1noc(C(F)(F)C(F)(F)F)c1-c1ccccc1

Procedure:
The title compouhd was obtained according to the same procedure as described in Example 32 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used.
Reaction SMILES: NC1C=C2C(C=CN2)=CC=1.[CH3:11][NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:11][NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1.[CH2:30]([O:37][C:38](=[O:39])[N:12]([CH3:11])[C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CNc1ccc2ccn(C)c2c1
Agent: Nc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OCc1ccccc1)c1ccc2ccn(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
N-Methyl-(1-methyl-1H-indol-6-yl)-amine was prepared from 6-amino indole in a manner similar to that described in Example 1 a. c) Methyl-(1-methyl-1H-indol-6-yl)-amine (50 mg, 0.33 mmole) was dissolved in methylene chloride (2 mL) and cooled to 0° C. Triethylamine (55 μl, 0.39 mmole) was added followed by benzylchloroformate (52 μL, 0.39 mmnole). The reaction was stirred at room temperature for 1 hr. The reaction mixture was washed with 0.1 N hydrochloric acid and the organic was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography in 25% ethyl acetate/hexane to give methyl-(1-methyl-1H-indol-6-yl)-carbamic acid benzyl ester (67 mg, 73%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:16])[O:8][C:7]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]#[N:15])=[CH:12][C:6]=2[O:5]1.[CH2:17]([N+](CC)(CC)CC)[C:18]1C=CC=CC=1.[Cl-].BrCCCl>O>[F:16][C:4]1([F:3])[O:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]3([C:14]#[N:15])[CH2:18][CH2:17]3)=[CH:12][C:6]=2[O:5]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCBr
Solvent: O
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl-acetonitrile, benzyltriethylammonium, chloride (3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70° C. The mixture was stirred overnight at 70° C. before the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give crude 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N.O.CC#N>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step H, from (3S*,4R*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (25.0 g, 41.1 mmol) and tetrabutylammonium fluoride trihydrate (19.4 g, 61.6 mmol) in THF (150 mL) as a colorless oil. MS: 495.2 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.84 min.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][C:6]1[CH:7]=[C:8]([CH:16](Br)[C:17]([CH3:19])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[S:3][C:16]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:14])[CH3:15])=[C:6]([Br:5])[CH:7]=2)=[C:17]([CH3:19])[N:4]=1
Reactant: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N)sc1-c1ccc(OC(C)C)c(Br)c1
Temperature: 40 °C
Yield: 66.4 %

Procedure:
Thiourea (65 mg, 0.857 in mol) was added to 1-(3-bromo-4-isopropoxyphenyl)-1-bromo acetone (200 mg, 0.571 mmol) in 0.5 mL of methanol and the mixture was heated to 40° C. The mixture was then heated to 80° C. And 1.0 mL of methanol was added to facilitate stirring. After refluxing 3 h, the reaction was transferred to a separatory funnel with 50 mL of ethyl acetate and 30 mL of saturate aqueous sodium bicarbonate, the layers were separated, and the organic layer was washed with 30 mL of brine. Drying over sodium sulfate and evaporation gave the crude product. Purification by flash chromatography, eluting with 30-50% ethyl acetate in hexane, gave 124 mg of the title compound as a white solid. Mass spectrum (NH3/CI): m/z=327 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13]CC2C=CC=CC=2)=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:21]1([O:1][C:2]2[C:3]([OH:13])=[CH:4][C:5]3[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: O=c1ccc2cc(O)c(OCc3ccccc3)cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OC3CCCC3)c(O)cc2o1
Reaction time: 3 h

Procedure:
50.0 g (186 mmol) of 6-hydroxy-7-phenylmethoxy-2H-1-benzopyran-2-one, 41.7 g (280 mmol) of cyclopentylbromide, 51.4 g (372 mmol) of potassium carbonate and 5.0 g of potassium iodide are agitated in 500 ml DMF for 18 h at 80° C. This is followed by filtration, evaporation, dissolution in chloroform, washing with water, drying over sodium sulfate and renewed evaporation: yield: 60.0 g (96%) of 6-(cyclopentyloxy)-7-(phenylmethoxy)-2H-1-benzopyran-2-one, fusion point 140°-141° C. (from isopropanol). Of this 15.0 g (45 mmol) in 200 ml ethanol are hydrogenated in the presence of 2.0 g Pd on active carbon (5%) for 3 h at 25° C. and 7 bar hydrogen pressure. After filtration the solvent is removed: yield 9.0 g (82%), fusion point 154°-155° C. (from isopropanol and TBME).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9].[H][H]>[Ni]>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: [H][H]
Reactant: CC#N
Reactant: CCC(N)CCN
Agent: [Ni]
Product: CCC1CCNC(C)N1
Temperature: 90 °C
Yield: 97.4 %

Procedure:
Sixty grams of 1,3-diaminopentane (96.7% purity, 0.569 mole), 60 g acetonitrile (1.46 moles) and 1 g of wet Raney® nickel (Raney 2800) catalyst were charged to a 300 ml stainless steel autoclave reactor. The mixture was stirred and heated at 90° C. and 500 psig hydrogen pressure for 6 hours. Capillary GC analysis of the cooled product indicated a 36% conversion of 1,3-diaminopentane and 97.4% yield of 2-methyl-4-ethylhexahydropyrimidine. The reactor was recharged with 25 ml (19.5 g) additional acetonitrile and run at 90° C. and 500 psig for 21 hours. Capillary GC analysis of the mixture indicated a 92.1% conversion of 1,3-diaminopentane and 98% yield of 2-methyl-4-ethylhexahydropyrimidine, b.p. 71° C./20 mm Hg. The structure was confirmed by comparison with a mass spectrum of the hexahydropyrimidine obtained by the condensation of 1,3-diaminopentane and acetaldehyde at 50° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>ClCCl>[N:27]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:11][CH:12]([NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:24])[CH2:13]2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 1.5 ml of dichloromethane, and 82 mg (0.55 mmol) of morpholine-4-carbonyl chloride and 58 μl (0.412 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 118 mg (90% of theory)
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](=[CH2:19])[C:15]([O:17]C)=[O:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2.C([O:24]O)(C)(C)C.CCCCCCCCC.CC(C)([O-])C.[K+]>C1COCC1>[F:1][C:2]1[C:3]([C:14]2([C:15]([OH:17])=[O:16])[CH2:19][O:24]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH3:13])=[N:5]2
Reactant: CC(C)(C)OO
Reactant: C=C(C(=O)OC)c1c(F)ccc2ncc(OC)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCCCC
Solvent: C1CCOC1
Product: COc1cnc2ccc(F)c(C3(C(=O)O)CO3)c2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of methyl 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-propenoate (5.45 g, 0.02 mol) (for a preparation, see Example 1(l)) in THF (150 ml) was cooled to 0° C. A 6M solution tert-butyl hydrogen peroxide in nonane (5.2 mL, 0.03 mol) was added dropwise followed by a 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol). During the addition the temperature was kept at 0° C. The reaction mixture was kept at 0° C. for 16 hours. Another 0.5 equivalent of the 1M solution of potassium tert-butoxide (10.39 mL, 0.01 mol) was added at 0° C. and the reaction mixture was kept for a further 2 hours. The reaction was quenched by addition of a 1M solution of HCl in methanol (20 mL). The reaction mixture was evaporated to dryness. The residue was partially dissolved in methanol. The organic layer was dried over magnesium sulphate, filtered, evaporated under vacuum and chromatographed on silica (required repeated chromatography), eluting with a 0-30% methanol in dichloromethane gradient to afford the product as a white solid (3.22 g, 59%)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[N:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (41 mg, 49%), MS (ISP) m/z=335.5 [(M+H)+], mp 280° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@@H:46]([C:55](O)=[O:56])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(=[O:42])[CH3:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@H:46]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:55](=[O:56])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30])(=[O:42])[CH3:41]
Reactant: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of the product of Example 2C (0.275 g, 0.517 mmol) in tetrahydrofuran (0.40 mL) were added the product from Example 174E (0.15 g, 0.519 mmol), DEPBT (0.233 g, 0.779 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.214 g, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (m, 15 H), 1.39 (s, 9 H), 1.47-1.56 (m, 2 H), 1.99 (s, 3 H), 2.72-2.79 (m, 3 H), 3.49 (s, 3 H), 3.62-3.65 (m, 2 H), 3.80-3.84 (m, 2 H), 4.05 (d, J=9.9 Hz, 1 H), 4.10-4.24 (m, 2 H), 4.94 (d, J=4.8 Hz, 1 H), 6.60-6.65 (m, 2 H), 7.10-7.21 (m, 8 H), 7.29-7.31 (m, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.77 (d, J=8.5 Hz, 1 H), 7.82-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.Cl>CN1C(=O)CCC1.O>[C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:27][CH:26]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Cl)c12
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 115 °C
Reaction time: 30 h
Yield: 86.4 %

Procedure:
266 (250 mg, 0.77 mol), N-(4-aminophenyl)benzamide (179 mg, 0.85 mmol), and HCl (19 μm, 0.77 mmol, 4.0 M in dioxane) were suspended in NMP (5 mL) and stirred for 30 h at 115° C. The reaction mixture was diluted with H2O. The resulting precipitate was filtered, washed with H2O and MeOH, and dried under vacuum to provide 267 (341 mg, 96% yield) as a white solid. LC-MS (M+H=465, obsd.=465).