Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][CH:23]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]1=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>ClCCl>[CH3:22][CH:23]1[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][C:24]1=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[O:36]
Reactant: CC1CC(C)(C)CC1=CCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1CC(C)(C)CC1=CCCCCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thereafter 2.5 equivalents of PDC (pyridinium dichromate) and 1 equivalent of 6-(2,4,4-trimethylcyclopentylidene)-hexan-1-ol in proportion 70:30 in dichloromethane are placed in a flask. The suspension is agitated vigorously at ambient temperature overnight. When the conversion is satisfactory (>95%), the reaction medium is filtered on Celite® and then on silica. The filtrate thus obtained is washed with an aqueous 1% HCl solution and then with a saturated aqueous sodium bicarbonate solution, and then with water. After drying on magnesium sulfate, filtration on paper and evaporation of the solvent, the crude product, containing two isomers in proportion 70:30 of 6-(2,4,4-trimethylcyclopentylidene)-hexanal, is distilled under reduced pressure: its boiling point is 59° C. at 0.2 torr.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[CH:29][N:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1>>[CH3:32][N:31]([CH3:33])[C:27]1[N:28]=[CH:29][N:30]=[C:25]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3][CH:4]3[CH2:8]2)[CH:26]=1
Reactant: CN(C)c1cc(Cl)ncn1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cc(N(C)C)ncn4)CC3C2)c(-n2nccn2)c1

Procedure:
The title compound was prepared utilizing (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Example 288, product from Step B) and 6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI) mass calcd. C22H26N8O2, 434.49; m/z found 435.2 [M+H]+.
Reaction SMILES: C([NH:18][CH:19]([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>C(Cl)(Cl)Cl.C(#N)C>[C:83]1([CH:19]([NH2:18])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=2[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reaction time: 5 h
Yield: 101.8 %

Procedure:
N-Fmoc-[phenyl (2,3,4-trioctadecanoxyphenyl)methyl]amine (830 mg, 684 μmol) obtained in Example 2 was dissolved in chloroform (10 ml) and acetonitrile (6 ml), diethylamine (2.04 ml, 1.97 mmol) was added dropwise and the mixture was stirred for 5 hr. The solvent was evaporated, and the residue was washed with acetonitrile (10 ml) to give [phenyl(2,3,4-trioctadecanoxyphenyl)methyl]amine (668 mg, 696 μmol, yield 99%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N1CCOCC1)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
17.6 Grams of a 50% solution of n-propane-phosphonic acid anhydride in methylene chloride are added in 3 portions, with stirring and the exclusion of moisture, to a solution of 2.4 g of β-phenylethylamine, 2.2 g of benzoic acid and 14 ml of N-ethyl morpholine in 25 ml of methylene chloride. The temperature rises to about +40° C. The mixture is cooled to room temperature, while stirring, and is worked up after 24 hours of standing by adding 350 ml of methylene chloride and extracting the solution three times with 50 ml each of water, saturated sodium carbonate solution and potassium bisulfate solution. The crude product crystallizes from the methylene chloride solution dried over magnesium sulfate. Said product is filtered off with suction together with a small amount of petroleum ether (boiling point 40° to 60° C.).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]([CH2:2][C:3]([CH3:5])=[CH2:4])[C:17](=[O:19])[CH3:18]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
At 25° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitrophenyl)acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reaction mixture was stirred at 25° C. overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na2CO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85%). ESI-MS 313 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH3:21].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:21])=[N:18][N:19]=[C:20]1[CH2:23][OH:24]
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 7, 2',5-dichloro-2-(3-methyl-4H-1,2,4-triazol-4 -yl)benzophenone was treated at 125° C. in xylene with paraformaldehyde to give 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone of melting point 193.5°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:25]([N:17]([CH3:18])[CH2:16][CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)[CH:26]=[CH2:27]
Reactant: CNCCC1(c2cccc(OC)c2)C=CCCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)CCC1(c2cccc(OC)c2)C=CCCC1

Procedure:
4.9 g of 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine are dissolved in 50 ml of acetone. Thereupon, 3.5 g of potassium carbonate are added, 1.8 ml of allyl bromide are slowly added dropwise while stirring, and the mixture is stirred overnight. Subsequently, the precipitate is removed by filtration, and the filtrate is evaporated, and rac. N-allyl-1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine remains as the residue. The hydrochloride of this compound melts at 114°-116° C. (after recrystallization from ethyl acetate/diisopropyl ether).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[CH3:14][C:15]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])[CH3:16]>O.O1CCOCC1.O1CCOCC1>[C:15]([O:18][C:19]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:20])([CH3:17])([CH3:16])[CH3:14]
Reactant: O=C(O)C1CNCCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-piperazine-carboxylic acid dihydrochloride (1.0 g, 4.92 mmol) in 20 mL of water/dioxane 1:1, NaOH 6N was added to adjust the pH to 11. A solution of BOC-ON® (1.34 g, 5.41 mmol) in dioxane (5 mL) was then added dropwise, while maintaining the pH=11 during the addition and the resulting solution was stirred overnight at room temperature. Another 0.134 g of BOC-ON® were added and the reaction mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was diluted with diethyl ether/water (60 mL). The phases were separated and the pH of the aqueous layer was adjusted to 7 by slow addition of HCl 1N. Evaporation of water under reduced pressure afforded the title compound as a white solid which was dried in a vacuum oven at 50° C. and used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2cccc(F)c2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccc(F)c3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(3-fluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 44 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.90 and 3.13 (2t, 2H), 3.56 and 4.17 (2t, 2H), 3.83-3.91 (4s, 6H), 4.47 and 5.07 (2s, 2H), 6.52 and 6.91 (2d, 1H), 6.72 and 7.02 (2d, 1H), 7.22-7.23 (m, 1H), 7.49-7.65 (m, 2H), 7.94-8.18 (m, 3H), 8.33-8.47 (m, 2H); MS (ESI) m/z 444 ([M+H]+).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-glutamic acid using Raney nickel or palladium/activated carbon (10%) as a catalyst. The product had a melting point of 94° C. and an RF -value of 0.61 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 85 parts by volume of methanol and 15 parts by volume of water).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]#[N:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:16][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[CH:3][CH:4]=1)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])#[N:27]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)C(F)(F)F)C(=O)NCC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@@H](c1ccc(-c2ccncc2)cc1)C(F)(F)C(F)(F)F)C(=O)NCC#N
Temperature: 95 °C

Procedure:
To a solution of N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1-(cyanomethyl)-L-leucinamide (82 mg, 0.18 mmol), 4-pyridylboronic acid (30 mg, 0.24 mmol) and PdCl2(dppf) (14 mg, 0.02 mmol) in 2.5 mL DMF was added 2M Na2CO3 (0.25 mL). The mixture was heated to 95° C. for 2.5 h, then cooled and partitioned between aq. Na2CO3 and ether. The aqueous phase was washed with brine and dried over MgSO4. Purification by silica gel chromatography (65% to 95% ethyl acetate/hexanes gradient) provided the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>CC(O)C>[OH:1][CH:2]([CH2:3][N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1)[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN2CCSCC2)cc1

Procedure:
A solution of 4-(oxiranylmethoxy)benzonitrile (10 g, 56.8 mmol) and thiomorpholine (7 g, 67.8 mmol) in 2-propanol (100 ml) was stirred over night at room temperature. Solvent was evaporated. The oily residue was dissolved in hydrochloric acid (2M, 50 ml) and extracted twice with diethylether. The acid aqueous solution was treated with sodium carbonate solution. The basic-aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over magnesium sulphate and solvent was evaporated. The crude oil was crystallized from diisopropylether; methylene chloride (9:1). Yield of the title compound (8.85 g; 56%) as colourless crystals with mp. 94°-95° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 609 %

Procedure:
A mixture of 3-hydroxy-1-ethynylbenzene (4.36 g, 37 mmol), benzylbromide (6.95 g, 4.1 mmol) and K2CO3 (10.2 g, 7.4 mmol) in acetanitrile (50 ml) is stirred at room temperature for 24 hr. The insoluble material is removed by filtration and filtrate is concentrated. The crude material is purified by flash chromatography (silica gel, hexane/EtOAc:95/5) to afford the title compound as a clear oil 5.2 g (68%). 1HNMR (400 MHz, CDCl3): δ (ppm) 3.05 (s, 1H), 5.05 (s, 2H), 6.98 (d, 1H) 7.00-7.50 (m, 8H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][CH:10]=1)=[O:7].ClC1C=CC=C(C(OO)=[O:43])C=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:14]=1)=[O:7])=[O:43]
Reactant: CSc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)c1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
5-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.043 mmol) obtained in Example 126 was dissolved in dimethylformamide (0.4 mL), the solution was added with m-chloroperbenzoic acid (ii mg, 0.03 mmol) at −20° C., and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was added with ethyl acetate at −20° C., the organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine. The solvent of the organic layer was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (8 mg, yield 38%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)([CH3:10])[CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:17][C:13]1[CH:12]=[C:11]([C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])([CH3:10])[CH2:8][OH:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(N)(CO)c1cccc(Br)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
2-Chloroacetyl chloride (2.24 g, 19.8 mmol) was added dropwise at 0° C. to a suspension of 2-amino-2-(3-bromo-phenyl)-propan-1-ol (3.8 g, 16.5 mmol), K2CO3 (4.55 g, 33 mmol) and dichloromethane (40 ml). The mixture was allowed to warm to room temperature over a period of approximately 3 h, washed with 1N hydrochloric acid and brine, dried with Na2SO4 and evaporated in vacuo to yield the crude title compound. 1H-NMR (400 MHz, CDCl3): 7.43 (m, 2H), 7.23 (m, 2H), 4.10-4.03 (m, 4H), 1.71 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CCO>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][N:21]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethyl-1H-pyrimidine-2,4-dione (step 3) (1 g, 2.97 mmol) in EtOH (12 mL) was treated with TEA (0.41 mL, 2.97 mmol) and tert-butyl 2-aminoethylcarbamate (commercial) (0.465 mL, 2.97 mmol). The mixture was heated to 100° C. for 1 h using microwave irradiation. After this time, a white precipitate had formed. The solid was collected via reduced pressure filtration and was washed with diethyl ether. The title compound was obtained as white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17]O[C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[CH:21](Cl)(Cl)Cl.CO>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][CH2:21][C:14]=3[CH:13]=1)[N:6]=[CH:5]2
Reactant: ClC(Cl)Cl
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Solvent: CO
Product: Nc1ccc2nc(-c3ccc4c(c3)CCO4)ncc2c1
Yield: 73 %

Procedure:
This compound was synthesized in 73% yield, according to the procedure described in example 1 for the synthesis of 6-amino-2-(1,3-benzodioxol-5-yl)-quinazoline. C16H13N3O, MW: 263.30. TLC(CHCl3/MeOH 9/1) Rf=0.65.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][NH:40][S:41]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1)(=[O:42])=[O:43]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNS(=O)(=O)c1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 33 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with (3-(N-methylsulfamoyl)phenyl)boronic acid (68 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (17 mg, 0.02 mmol) and 1.12 ml 1,2-dimethoxyethane and 0.28 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 40 mg (33% yield, 77% purity) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>ClCCl.CS(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH:14]=[O:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Yield: 90.3 %

Procedure:
To a suspension of N-Boc-L-isoleucinol (5 g, 23 mmol) in dichloromethane (250 mL) and DMSO (50 mL) at 0° C. was added TEA (10 mL, 73 mmol) followed by slow addition of the solution of sulfur trioxide pyridine complex (11 mL, 69 mmol) in DMSO (50 mL) via syringe. The reaction mixture was concentrated and was diluted with ether (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL), which was then washed with brine (150 mL), water (150 mL) and NaHCO3 (150 mL) sequentially. The organic layers were dried over MgSO4, filtered and concentrated. The residue was dried on pump to afford ((1S,2S)-1-formyl-2-methyl-butyl)-carbamic acid tert-butyl ester (4.47 g, 90% yield) as light-yellow clear liquid.
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.CCN(CC)CC>ClCCCl>[CH3:2][C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., tert-butyldiphenylchlorosilane (50 g) was added slowly to a solution of p-hydroxybenzaldehyde (22 g) and Et3N (42 mL) in 1,2-dichloroethane (400 mL) and the mixture was stirred at room temperature a few hours. After the usual work up, the product was purified by flash chromatography on silica using EtOAc:hexane 1:10 and was used as such for Step 2.