Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([C:14](=[NH:2])[NH2:15])[CH:11]=[CH:10][N:9]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a suspension of ammonium chloride (10.7 g, 200 mmol) in 250 mL of dry toluene. was added a 2 M solution of Al(CH3)3 (100 mL, 200 mmol) in toluene dropwise under nitrogen at 0° C. The resulting reaction mixture was stirred at rt until no more evolution of gas was observed and then 2-chloropyridine-4-carbonitrile (13.86 g, 100 mmol) was added. The mixture was stirred at 90° C. overnight. It was then cooled down to 0° C. and 300 mL of methanol were added with subsequent stirring for 1 h at rt. After filtration, the solid was washed with methanol for several times, the solution was evaporated to dryness under vacuum. The residue was washed with methanol to give 2-chloropyridine-4-carboximidamide. (18.3 g, 95%). 1HNMR δ (400 MHz, d6-DMSO): 8.70 (dd, J=4.8, 0.4 Hz, 1H), 8.00 (dd, 0.4 Hz, 1H), 7.84 (dd, J=5.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.53 (t, J=8.1 Hz, 1H); MS (ESI) m/z (M+H)+ 156.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[S:13])[NH:11][CH3:12])#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:44].[Na+].[K+]>ClCCl>[CH:1]([CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[S:13])[NH:11][CH3:12])=[O:44]
Reactant: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=CC#N
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNC(=S)C1(c2cnc3ccccc3c2)CCCCC1=CC=O
Temperature: 10 °C

Procedure:
A solution of (±)-2 -cyanomethylene-N-methyl-1-(quinolin-3 -yl)cyclohexane carbothioamide (1 g, 3.1 mmol) in dichloromethane (25 ml) was cooled to -20° C. and treated with a 1 M solution of diisobutylaluminium hydride in toluene (3.1 ml, 3.1 mmol). The mixture was allowed to warm to 10° C. over 90 mins. Dichloromethane (50 ml) was added to the reaction mixture followed by an aqueous solution of Rochelle salt (50 ml). The layers were separated and the organic layer was washed with an aqueous solution of Rochelle salt (50 ml). The organic extract was dried over magnesium sulphate and concentrated in vacuo to yield a yellow oil. Purification by flash chromatography over silica gel, eluting with a 1:1 (v/v) mixture of ethyl acetate/hexane yielded (±)-2 -formylmethylene-N-methyl-1-(quinolin-3 -yl)cyclohexane carbothioamide (300 mg, 0.93 mmol) as a pale yellow solid, m.p. 149°-151° C.;
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:24])([F:23])[C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[C:8]([F:16])([F:15])[C:9](F)([F:13])[CH2:10][CH2:11]I>O1CCCC1>[F:13][C:9]([C:8]([F:16])([F:15])[C:7]([F:18])([F:17])[C:6]([F:20])([F:19])[C:5]([F:22])([F:21])[C:4]([F:24])([F:23])[F:3])=[CH:10][CH2:11][NH:2][CH3:1]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CN
Solvent: C1CCOC1
Product: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.44 g of methylamine is condensed in a solution of 2.82 ml of 1,1,1,2,2,3,3,4,4,5,5,6,6 tridecafluor-8-iod-octane in 20 ml of anhydrous tetrahydrofuran at −40° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −30° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is mixed with diethyl ether, washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 2.23 g of (3,4,4,5,5,6,6,7,7,8,8,8-dodecafluor-oct-2-enyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:21][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)=[O:20])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1cccc(C(=O)OC2CCCCO2)c1

Procedure:
A mixture of 7 g. 3-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and evaporated. The residue is collected and crystallized from methylcyclohexane to yield the product as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.[CH:27]1C2CC3C(=CC=CC=3)NC=2C=CC=1.[H-].[Na+].Br.NC1N=C(N)C2C(=NC=C(CBr)N=2)N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=4)[N:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: Br
Agent: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(CN3c4ccccc4Cc4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopteridin-6-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminopteridin-6-yl; W=CH2; N=X; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10 dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:32]3[C:23](=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)[NH:22][C:21](=[O:33])[CH2:20][C:19]2=[O:34])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:32]4[C:23](=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[N:27][CH:26]=[CH:25]5)[NH:22][C:21](=[O:33])[CH2:20][C:19]3=[O:34])=[CH:14][CH:13]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2cnccc32)cc1
Reactant: O=C(O)c1cccnc1Cl
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccnc3Cl)cc2)c2ccc3cnccc3c2N1
Yield: 87.4 %

Procedure:
By using 2-chloronicotinic acid (32 mg, 0.2 mmol), and 5-(4-aminophenyl)-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione (6 mg, 0.02 mmol), the title compound (8 mg, yield 85%) was obtained as pale brown powder in the same manner as that of Example 149.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[C:16]([F:29])=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[C:16]([F:29])=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH3:35])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3cc(F)c(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCc2c(c3cc(F)c(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
To a solution of 4-(benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 mL) were sequentially added formaldehyde (37% aqueous solution, 22 μL, 0.74 mmol) and NaBH(OAc)3 (316 mg, 1.49 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% aqueous LiCl, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(10:1:0.1 CH2Cl2/MeOH/NH4OH), 0:1 to 1:1) gave 4-(benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (78 mg, 38%) as a yellow solid. The free base was converted to the HCl salt using 1.25M HCl in methanol providing the title compound (75 mg, 95%) as a off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.53-7.33 (m, 7H), 7.27 (d, J=10.5 Hz, 1H), 7.28 (dd, J=7.8, 2.4 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 3.79 (br s, 2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H), 2.64 (s, 3H); ESI MS m/z 418 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=14.5 min.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[O:26][CH3:27].[Li+].[OH-]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2])=[C:7]([O:26][CH3:27])[CH:8]=3)[N:15]=2)=[CH:20][CH:21]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [F-].[K+].CN1CCCC1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]=[C:18](I)[C:11]=12.C[Si](C)(C)[C:32]([F:35])([F:34])[F:33]>[Cu]I.C(OC)(C)(C)C.CN(C=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]=[C:18]([C:32]([F:35])([F:34])[F:33])[C:11]=12
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ccnc32)cc1
Agent: [Cu]I
Agent: CN1CCCC1
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C(F)(F)F)c3c(Cl)ccnc32)cc1
Temperature: 220 °C
Reaction time: 0.33 h

Procedure:
Under an atmosphere of protective gas (argon), 23.1 g (0.398 mol) of dry potassium fluoride and 75.7 g (0.398 mol) of copper(I) iodide are ground with one another and, under high vacuum and with shaking, heated at 220° C. for 10 minutes, until there is a slight greenish discoloration. The sintered mixture of potassium fluoride and copper(1) iodide together with 170 ml of absolute N-methylpyrrolidine and 170 ml of absolute DMF is initially charged in a reaction flask under an atmosphere of protective gas (argon), and 86 g (0.199 mol) of 4-chloro-1-(toluene-4-sulfonyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine are then added a little at a time and with stirring at 20° C., whereupon a light-gray suspension is formed. Over a period of 20 minutes, 62.1 g (0.437 mol) of trimethyltrifluoromethylsilane are added dropwise to the reaction mixture, and the mixture is stirred at 20° C. for 18 h. After complete conversion (conversion monitored by GC), the reaction mixture is poured into 2000 ml of methyl tert-butyl ether, the organic phase is decanted and the residue is once more dispersed in 1000 ml of methyl tert-butyl ether. The combined organic phases are washed three times with in each case 2000 ml of water and then dried over magnesium sulfate. Filtration and removal of the volatile components under water pump vacuum gives 50.1 g (67% of theory) of the target compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:4](=[O:6])[CH2:3][CH2:2][OH:1])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)CCO
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CCO
Yield: 24 %

Procedure:
The procedure described in Example 1 was repeated using 3-hydroxypropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 24% yield; NMR spectrum (DMSO-d6) 2.13-2.26 (m, 2H), 2.65-2.79 (m, 2H), 3.30 (s, 3H), 3.87-3.97 (m, 2H), 4.13-4.25 (m, 1H), 4.34-4.61 (m, 2H), 5.31 (s, 2H), 7.15 (d, 1H), 7.25 (d, 1H), 7.32-7.39 (m, 2H), 7.53-7.57 (m, 1H), 7.60 (d, 1H), 7.70-7.76 (m, 1H), 7.86-7.92 (m, 2H), 8.42 (s, 1H), 8.61 (d, 1H), 9.70 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:10](=[O:11])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: CNOC
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 306 mg (1.25 mmol) of (2S)-(3,4-dichlorophenyl)-4-pentenoic acid and 202 mg (1.50 mmol) of 1-hydroxybenzotriazole hydrate in 10 mL of methylene chloride was cooled to 0° C. and treated with 287 mg (1.50 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The cooling bath was removed and after 45 min. a solution of 365 mg (3.75 mmol) of N,O-dimethylhydroxylamine hydrochloride and 522 μl (3.75 mmol) of triethylamine in 10 mL of methylene chloride was added via cannula. The mixture was then stirred at 22° C. for 4 hours and then quenched with 10 mL of water and diluted with 8 mL of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2×10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 75 g of silica gel using 1:9 v/v ethyl acetate/ hexane as the eluant afforded 319 mg (89%) of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]4[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]4)=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])=[N:20][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
A mixture of 0.056 g (0.00013 mole) of 4-(9-benzyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid, 0.054 g (0.00014 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.079 mL (0.00046 mole) of ethyldiisopropyl amine and 2.0 mL of dimethylformamide was stirred for 5 minutes and then 0.022 g (0.0002 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.045 g of 4-(9-benzyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-22) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].[CH3:44][C:45]([CH3:47])=[O:46].ClC(OC)=O>CN(C)C=O>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].[CH2-:44][C:45]([CH3:47])=[O:46]
Reactant: CC(C)=O
Agent: COC(=O)Cl
Agent: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Solvent: CN(C)C=O
Product: [CH2-]C(C)=O
Temperature: 25 °C

Procedure:
15 grams of rutin are dissolved in 60 cc of dimethylformamide. After addition of 100 cc of acetone, 15 cc of methyl chloroformate are added dropwise while agitating the mixture. Since the reaction is exothermic, the mixture is maintained at ambient temperature with cooling. At the end of 6 hours, the mixture is evaporated under vacuum. The residue is taken up in 500 cc of water. The solution is extracted with ether. The residual aqueous phase is extracted with ethyl acetate. After evaporation of the organic phase, about 10 grams of rutin acetonide is obtained, which can then be recrystallized.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:32][C:33]1[C:34]([C:40]([NH:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:41])=[N:35][C:36](Br)=[CH:37][N:38]=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]>[NH2:32][C:33]1[N:38]=[CH:37][C:36]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][CH2:14][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:22][CH:21]=2)=[N:35][C:34]=1[C:40](=[O:41])[NH:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reactant: COCCCN(CCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C

Procedure:
A mixture of the product of step (iv) (250 g, 0.58 mol), 3-amino-6-bromo-N-(pyridin-3-yl)pyrazine-2-carboxamide (220 g, 0.75 mol), Na2CO3 (183 g, 1.73 mol) and Pd(dppf)Cl2 (25.30 g, 35 mmol) in DMF (3 L) was stirred and degassed with N2 three times. The mixture was stirred at 70˜80° C. under N2 for 24 hours. The mixture was filtered and the filtrate concentrated to in vacuo to remove DMF. EtOAc (1.5 L) and H2O (800 mL) were charged and stirred for 1 hour at 10-25° C. The suspension was filtered, the organic phase was concentrated in vacuo and purified by column chromatography (PE: EtOAc=3:1-1:3). The crude product was re-crystallized from EtOAc-MeOH and filtered, the yellow solid was washed by EtOA and dried under reduced pressure. The subtitle compound (v) was obtained (pale yellow solid, 160 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47]3)[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:48]2[CH2:47][C:46]3[C:50](=[CH:51][CH:52]=[C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)[CH:45]=3)[CH2:49]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)c(O)cc1O
Reactant: CN1CCN(c2ccc3c(c2)CNC3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3c(c2)CN(C(=O)c2cc(Cl)c(O)cc2O)C3)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-2,4-dihydroxy-benzoic acid (176 mg, 0.93 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (179 mg, 0.93 mmol) then HOBt (126 mg, 0.93 mmol). After 45 min, the solution of the activated acid was added to a mixture 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride (290 mg, 0.78 mmol) and triethylamine (0.28 mL, 2 mmol) then the mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and brine then dried (MgSO4), combined and concentrated. Some insoluble material remained and this was dissolved in 1N hydrochloric acid and methanol then combined with the organic extracts. The pH was adjusted to 14 with solid sodium hydroxide and the mixture allowed to stand overnight. The pH was adjusted to 7 with 1N hydrochloric acid and the resulting precipitate was filtered off then subjected to purification by preparative HPLC to afford the title compound as a red solid. This was converted to its hydrochloride salt by treatment with 4M HCl in dioxane, concentration in vacuo and trituration with ether which gave a brown solid (91 mg, 27%). 1H NMR (DMSO-d6) 11.10 (1H, br.s), 10.50 (1H, br.s), 7.26-7.15 (2H, m), 7.02-6.93 (2H, m), 6.69 (1H, s), 4.72-4.61 (4H, m), 3.78-3.72 (2H, m), 3.45 (2H, br.s), 3.12 (4H, br.s), 2.78 (3H, s). MS: [M+H]+ 386/388.