Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35]CC)=[O:34].[OH-].[Na+].Cl>CN(C)C=O.O>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:32][C:33]([OH:35])=[O:34])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1(c1ccccc1)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)(C1CCCC1)C2
Temperature: 100 °C

Procedure:
A stirred mixture of 2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (1.10 g., 0.003 mole), potassium carbonate (0.85 g., 0.006 mole) and ethyl bromoacetate (1.02 g., 0.006 mole) in dimethylformamide (20 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (20 ml.)-10 N sodium hydroxide solution (1.2 ml., 0.012 mole) and heated at 100° C. for one hour. The reaction mixture is added slowly to water (300 ml.)-12 N hydrochloric acid (5 ml.) to precipitate 680 mg. of (1-oxo-2-cyclopentyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 184°-186° C. after crystallization from nitromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH:10]([CH3:23])[N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C(N(CC)CC)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:25])[CH:10]([CH3:23])[N:9]=1
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=S

Procedure:
32 g of (+)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 450 ml of absolute dioxane and treated with 21 g of phosphorus pentasulfide and 15 ml of triethylamine. The mixture is heated to reflux for 20 minutes, cooled with ice and concentrated on a rotary evaporator. The residue is treated with 10% bicarbonate solution and ethyl acetate and the ethyl acetate phase is washed twice with 10% bicarbonate solution, dried with sodium sulfate, filtered and concentrated. Crystallisation of the residue from ethanol yields racemate. By concentration of the mother liquor, there is obtained crude (+)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-thione which exhibits a rotation of [α]25D =+319.1° (in methylene chloride, 1%).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CC(C)c1ccc2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc2c(Cl)ncnc2c1
Yield: 97 %

Procedure:
The product of Example 431E (100 mg, 0.5313 mmol) in phosphorous oxychloride (2 mL) was heated under a nitrogen atmosphere at reflux for one hour. The reaction was cooled and concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium hydrogencarbonate (2×25 mL), water (25 mL), and brine (25 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a yellow oil (107 mg, 0.5177 mmol, 97%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 3.14-3.29 (m, 1 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 7.93 (s, 1 H) 8.22 (d, J=8.46 Hz, 1 H) 9.07 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH2:51]([NH:54][CH2:55][C:56]#[CH:57])[CH2:52][CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([N:54]([CH2:55][CH2:56][CH3:57])[CH2:51][C:52]#[CH:53])=[O:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: C#CCNCCC
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(CCC)C(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which N-propylpropargylamine (0.804 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.25 g of the title compound as the dihydrochloride sesquihydrate, m.p. 172°-4° C.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:30])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[Pd]>[OH:8][NH:9][C:10](=[O:30])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[CH:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=1
Reactant: CC(C)C(C(=O)Nc1ccc(C(=O)NOCc2ccccc2)cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(C(=O)Nc1ccc(C(=O)NO)cc1)c1ccccc1
Yield: 90 %

Procedure:
Compound 3 (6.1 g; 15.2 mmol) was dissolved in 1:1 methanol/THF (120 ml), and 10% palladium on charcoal (0.6 g, 10% w/w) was added. The mixture was treated with hydrogen under atmospheric pressure for 2 h, and filtered. The solvent was evaporated and the residue was recrystallized with ethyl acetate, yielding 4.2 g (90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH:29]1([C:26]2[CH:25]=[N:24][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[C:4]([F:21])[CH:3]=3)=[N:28][CH:27]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2F)C1
Reactant: Clc1ncc(C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C4CC4)cn3)cc2F)C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
(R)-tert-Butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate (300 mg), 2-chloro-5-cyclopropylpyrimidine (188 mg, CAS 166740-44-9) and cesium carbonate (495 mg) were combined with dioxane (8 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (35.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (31.4 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 3 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 55% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylate (180 mg, 43%) as a yellow solid. MS (ISP): 415.2 ([M+H]+).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([NH:7][CH:8]([CH:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18])[C:9]([OH:11])=[O:10])=[O:6])[CH3:4].C(=O)([O-])O.[Na+].[BH4-].[Na+].Cl>O>[NH2:2][C@H:3]([C:5]([NH:7][CH:8]([CH:12]1[CH2:16][CH:15]([OH:17])[NH:14][C:13]1=[O:18])[C:9]([OH:11])=[O:10])=[O:6])[CH3:4]
Reactant: C[C@H](N)C(=O)NC(C(=O)O)C1CC(=O)NC1=O
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: C[C@H](N)C(=O)NC(C(=O)O)C1CC(O)NC1=O
Reaction time: 1 h

Procedure:
In 20 ml of water was dissolved 3.2 g of L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine hydrobromide and the solution was adjusted to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate and cooled to 0°-5° C. To this solution was added 1.5 g of sodium borohydride all at once. The mixture was stirred at the same temperature for one hour, while kept maintaining at pH 8.9-9.2 with 2 N hydrochloric acid. The reaction mixture was adjusted to pH 4.0 with 2 N hydrochloric acid, diluted with 200 ml of water and adsorbed on a column (150 ml) of Amberlite IRA-68 (OH- -form). After the column was washed with water, elution was carried out with 0.2 N acetic acid. The eluate was concentrated to dryness under reduced pressure and the resultant powder was subjected to column chromatography on activated carbon and eluted with water. The eluate was concentrated under reduced pressure and lyophilized to give L-alanyl-2-(5-hydroxy-2-oxopyrrolidin-3-yl)glycine as a white powder.
Reaction SMILES: [Na].C(O)C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Cl:27])=[CH:15][C:14]=1[C:28](=[O:30])[CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:31](OCC)(=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([OH:37])=[CH:29][C:28]([C:14]1[CH:15]=[C:16]([Cl:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:13]=1[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:30])[CH3:36]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
Sodium metal (1.35 g, 0.058 mol) was added in small pieces over a period of 20 minutes to stirred anhydrous ethanol under a nitrogen atmosphere. The reaction mixture was then stirred for a further 10 minutes until all the sodium had reacted to give a homogeneous solution. 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-ethanone (10.0 g, 0.027 mol) was added in portions over 2-3 minutes and the resulting suspension was stirred for 5 minutes prior to addition of diethyl oxalate (6 ml, 0.043 mol) which afforded a thicker, yellow precipitate. The reaction mixture was heated to reflux (giving homogeneous brown solution) for 4 hours, then allowed to cool to room temperature and acetic acid (6 ml) was added. The resulting which solid forms was triturated, filtered, washed with ethanol and dried to give a yellow solid (12.0 g, 95%). 1H NMR (400 MHz, CDCl3) δ 1.2 (t, 3H), 4.19 (q, 2H), 5.05 (s, 2H), 5.10 (s, 2H), 6.50 (s, 1H), 7.22-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([C:9](I)=[C:10]([CH2:12][O:13][CH3:14])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]4=[N:11][C:10]=3[CH2:12][O:13][CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(OC)cccn2c1I
Product: COCc1nc2c(OC)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 65.5 %

Procedure:
[step 4] Using 8-methoxy-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (500 mg, 1.57 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (230 mg, 0.786 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[8-methoxy-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 66%) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:16]#[N:17])[C:10]=2[CH:9]=[CH:8]1>[Ni].N.CO>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[CH:12][N:13]=[CH:14][C:15]([CH2:16][NH2:17])=[C:10]2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C#N)cncc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(CN)cncc21
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (683 mg, 2.5 mmol) in a solution of NH3/MeOH (7 N, 20 mL) was added Raney nickel (300 mg). The mixture was stirred under hydrogen for 3 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford 673 mg (97.1%) of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine as a yellow oil. MS (ESI): m/z=278.1 [M+1]+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[C:6]([CH3:14])[N:5]=1>CCCCCC>[NH2:2][C:1]1[N:7]([CH3:8])[CH:6]([CH3:14])[N:5]=[C:4]([Cl:3])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: CCCCCC
Product: CC1N=C(Cl)C([N+](=O)[O-])=C(N)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Methylamine (15.4 mL 1M in THF, diluted with 10 mL of hexane) is added dropwise to a solution of 4,6-Dichloro-2-methyl-5-nitropyrimidine (3.2 g, 15.4 mmol) in Hexane (30 mL). After addition, the reaction mixture is stirred at room temperature for one hour, and concentrated in vacuo to a solid. After the solid is dissolved in 50 mL of CH2Cl2, the resultant solution is washed with 0.1 N HCl (20 mL) and water (20 mL), dried over Na2SO4 and concentrated to a yellow solid. 1H NMR (CDCl3): δ 7.7 (bs, 1H), 3.10 (d, 3H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C1(C)C=CC=CC=1.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25](=[O:39])[C:26](=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[N:27]=2)=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14]>O>[OH:4][CH2:3][CH2:2][NH:1][C:25](/[C:26](/[NH:27][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:22][CH:21]=1)=[CH:28]\[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:34]=1)=[O:39]
Reactant: NCCO
Reactant: CC(C)COc1ccc(C2=NC(=Cc3ccc(OC(C)C)cc3)C(=O)O2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)COc1ccc(C(=O)N/C(=C/c2ccc(OC(C)C)cc2)C(=O)NCCO)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
2-Aminoethanol (50 μL, 0.828 mmol) was added to a solution of toluene (2.0 mL) containing 2-(4-isobutoxyphenyl)-4-(4-isopropoxybenzylidene)-1,3-oxazol-5(4H)-one (151 mg, 0.398 mmol, a mixture of 4E isomer/4Z isomer=4.6/1) prepared in Example 103 (103a). The mixture was stirred at 50° C. for 15 minutes, and then water was added to this reaction solution. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by thin layer chromatography for separation (ethyl acetate) to give 37 mg of the title compound (white solid, yield: 21%). [In addition, 53 mg of the corresponding Z isomer of the title compound (white solid, yield: 30%) was given.]
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:22][CH:23]=[C:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C.CN(C)C=O.O>C(OCC)(=O)C>[O:22]=[C:23]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:10][C:11]=3[C:2]2=[N:1][CH:30]=[C:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NC(=O)CC(C)(C)C)ccc3ncn2c1=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (12.2 g), diethyl ethoxymethylenepropandioate (15.3 g) and N,N-dimethylformamide (50 ml) was stirred at 150° C. for 2 hours. The reaction mixture was cooled to ambient temperature. After adding water, the resultant mixture was extracted with chloroform. The chloroform layer was washed twice with water and once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, to which was added ethyl acetate. Insoluble materials were separated by filtration and dried to give ethyl 4-oxo-10-(3,3-dimethylbutanamido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.7 g) melting at 253°-254° C. Further, the filtrate was concentrated under reduced pressure to give a residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl [{6-(3,3-dimethylbutyramido)4-quinazolinylamino}methylene]propanedioate (10.1 g).
Reaction SMILES: [C:1]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:14][C:15]=1[N:16]=[N:17][N:18]([CH3:20])[CH3:19])([O:3]CC1C=CC=CC=1)=[O:2].C(=O)=O>CO.[Pd]>[CH3:19][N:18]([CH3:20])[N:17]=[N:16][C:15]1[NH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:12][C:11]=1[C:1]([OH:3])=[O:2]
Reactant: CN(C)N=Nc1[nH]c(-c2ccccc2)nc1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: CN(C)N=Nc1[nH]c(-c2ccccc2)nc1C(=O)O

Procedure:
A solution of 4-carbobenzoxy-5-(3,3-dimethyltriazeno)-2-phenyl imidazole (1.0 gm) in methanol (50 ml) was saturated with carbon dioxide, and 10% palladium on charcoal (100 mgs) added. The mixture was hydrogenated at room temperature and pressure. A volume of 60 ml of hydrogen was absorbed in 1 hour 20 minutes.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:11]=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH:30]1[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[NH:35][C:34]=2[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCCCCCCCC>[Cu].C(Cl)(Cl)Cl.CS(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[C:12]1[CH:11]=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:35]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=4[C:42]4[CH:30]=[N:31][CH:32]=[CH:33][C:34]3=4)[N:7]=2)[CH:13]=1
Reactant: Brc1cccc(-c2cc(-c3ccc4ccccc4c3)cc(-c3ccccn3)n2)n1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cc(-c3ccc4ccccc4c3)cc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)n2)nc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To 4.2 g of the resulting 6-bromo-4′-(naphthalen-2-yl)-[2,2′;6′,2″]terpyridine were added 1.6 g of 5H-pyrido[4,3-b]indole, 0.3 g of a copper powder, 4.0 g of potassium carbonate, 0.3 mL of dimethyl sulfoxide, and 10 mL of n-dodecane, followed by heating and stirring at 150° C. for 8 hours. After cooling to room temperature, 80 mL of chloroform was added thereto to remove an insoluble matter by filtration, and the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: NH silica gel, eluent: hexane/chloroform) to obtain 2.2 g (yield, 43%) of 4′-(naphthalen-2-yl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 27) as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:12][NH:13][C:14]1[C:19]([Cl:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=1)C1C=CC=CC=1.Cl>C(O)C>[Cl:20][C:19]1[C:14]([NH:13][CH2:12][C:11]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:9]([OH:8])[CH:10]=2)=[N:15][C:16]([CH3:22])=[N:17][C:18]=1[CH3:21]
Reactant: COc1ccc(CNc2nc(C)nc(C)c2Cl)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CNc2nc(C)nc(C)c2Cl)cc1O
Yield: 81.2 %

Procedure:
In analogy to the method described in example B1, 3.0 g (7.8 mmol) of (3-benzyloxy-4-methoxy-benzyl)(5-chloro-2,6-dimethylpyrimidin-4-yl)amine (from example A4) are reacted with 30 ml of 12.5N hydrochloric acid in 30 ml of ethanol. Extraction with ethyl acetate at a pH of 8 gives, after concentration, a solid residue which is chromatographed on silica gel (mobile phase: toluene/dioxane=5:1). Crystallization from toluene/methanol gives 1.86 g (72%) of the title compound as a beige crystallizate. m.p.: 165-168° C.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.Cl.[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH:42][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[O:19])=[CH:15][CH:16]=2)[C:7]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:5])[CH:39]([CH3:41])[CH3:40]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CCOC(=O)c1onc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)c1-c1ccccc1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)c1-c1ccccc1)C(C)C
Yield: 88.7 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-4-phenyl-isoxazole-5-carboxylic acid ethyl ester and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 88.7% yield. Mass (ES+): 531 (M++1); 1H NMR (DMSO-d6) δ: 0.79 (m, 6H), 2.02 (m, 1H), 3.65 (s, 3H), 4.29 (m, 1H), 7.11 (t, 1H), 7.43-7.47 (m, 2H), 7.52 (m, 3H), 7.55 (d, 2H), 7.67 (d, 2H), 7.81 (m, 2H), 8.74 (s, 1H), 8.93 (s, 1H), 9.25 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[S:14][C:13]([CH2:15][CH2:16][CH3:17])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[S:14][C:13]([CH2:15][CH2:16][CH3:17])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCc1nc2cnc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1nc2cnc3cc(OCc4ccc(F)cc4)ccc3c2s1
Reaction time: 0.5 h

Procedure:
A mixture of 7-hydroxy-2-propylthiazolo[4,5-c]quinoline (0.88 g, 3.6 mmol) and cesium carbonate (2.35 g, 7.20 mmol) in DMF (50 mL) was stirred for 30 min, then 4-fluorobenzylbromide (0.50 mL, 4.0 mmol) was added. After 2 h, the mixture was concentrated in vacuo to remove the DMF. The resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated to a light yellow solid. The solid was recrystallized from heptane and pure 7-(4-fluorobenzyloxy)-2-propylthiazolo[4,5-c]quinoline was isolated as a tan solid (0.86 g, 68%).