Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH3:24])[C:18]([C:25](OCC)=[O:26])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH3:24])[C:18]([CH2:25][OH:26])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CO
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a suspension of lithium aluminum hydride (160 mg) in tetrahydrofuran (14 mL), ethyl 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E3, 450 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, lithium aluminum hydride (80 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and an aqueous solution of the Rochell salt were added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The insoluble matter was removed by filtration through Cerite. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 90% ethyl acetate in methanol) to obtain (2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methanol (E13, 212 mg).
Reaction SMILES: [N:1]1[NH:2][C:3]([C:10]([OH:12])=O)=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[NH:2][N:1]=[C:9]4[C:4]=3[CH2:5][CH2:6][CH2:7][CH2:8]4)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1[nH]nc2c1CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1[nH]nc2c1CCCC2
Yield: 65.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by flash chromatography. Yield 65.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 1.55-1.71 (m, 4H), 2.53-2.60 (m, 4H), 4.27 (dd, 1H), 4.35 (dd, 1H), 4.38-3.46 (m, 1H), 7.00 (d, 1H), 7.83-7.87 (m, 2H), 7.90-7.97 (m, 2H), 12.66 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10](CC([O-])=O)[CH2:9]1.C(=O)([O-])[O-:27].[K+].[K+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:27])[CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC(=O)[O-])C[C@@H](OC2CCCCO2)C1
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate (6, 3.5 parts, 9.16 mmol) was dissolved in dry methanol (25 parts). To the solution anhydrous potassium carbonate (0.828 parts, 6 mmol) was added and the mixture was stirred at room temperature for 2 hr. Methanol was removed under vacuum and residue was extracted several times with dichloromethane. Dichloromethane layers were combined and washed with water followed by brine wash. It was dried on anhydrous sodium sulfate. Solvent was removed under vacuum and residue was purified by flash column chromatography to yield 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol (7, yield 3 parts, 96%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:17])[C:13]([CH3:16])=[CH:14][CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[C:13]([CH3:16])=[CH:14][CH3:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=C(C)C(O)c1cc(-c2ccccc2)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC=C(C)C(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolved in 100 m of benzene were 5.4 g (23.6 mmol) of 3 -phenyl-5-(1-hydroxy-2 -methyl-2 -butenyl)isoxazole, followed by the addition of 21.0 g (0.24 mol) of manganese dioxide. The mixture was stirred at room temperature for 24 hours. An insoluble material was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: 30:1 n-hexane/ethyl acetate), whereby 3-phenyl-5-(2-methyl-2-butenoyl)isoxazole was obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][C:25]=1[CH3:26].ClC1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH3:14]
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(Cl)c1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 29 e]) was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl.CO>[Br:14][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([NH:9][CH3:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: CNc1nc(OC)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CNc1nc(OC)c(Br)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6-Methoxy-N-methyl-3-nitropyridin-2-amine (7 g, 38 mmol) in 150 mL dichloromethane and 50 mL methanol were combined with tetrabutylammonium-tri-bromide (20.3 g, 42.0 mmol). The mixture was stirred at ambient temperator for 2 h. The mixture was poured into water, filtered and washed with water and ethanol and reacted without further purification.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].N1C=CC=CC=1.[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1>C(OCC)C>[NH2:13][C:14]1[C:15]([F:38])=[CH:16][C:17]([F:37])=[C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:19]=1
Reactant: NCC(F)(F)F
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(F)(F)F)c(Cl)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
2,2,2-Trifluoroethylamine (50 mg) and pyridine (300 ml) were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was stirred at 40° C. for 2 days. Additional 2,2,2-trifluoroethylamine (50 mg) was added, and the mixture was stirred at 40° C. for 2 days. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and solids deposited were collected by filtration and washed with ethanol to obtain the title compound (90 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)(=[O:36])=[O:35])=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:40][CH:41]=2)(=[O:36])=[O:35])=[CH:28][CH:27]=1
Reactant: O=S(=O)(NCc1ccncc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-4-ylmethyl)-amide (example B.55) (167 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (115 mg, 38%). MS (ISN) 606.2 [(M−H)−]; mp 170° C.
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.C1(C)C=CC=CC=1.[Cl:19][CH2:20][C:21](OC(=O)CCl)=O>O>[CH2:7]([C:8]1[N:9]=[C:21]([CH2:20][Cl:19])[O:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(Cc1ccccc1)=NO
Solvent: Cc1ccccc1
Solvent: O
Product: ClCc1nc(Cc2ccccc2)no1

Procedure:
A solution of 40 g. (0.27 mole) of crude phenylacetamide oxime in 200 ml. of dry toluene is treated with 45.9 g. (0.27 mole) of chloroacetic anhydride in 100 ml. of toluene. The resultant mixture is then refluxed and the water formed is removed by means of a Dean Stark trap. The mixture is refluxed for 3-4 hours after which it is cooled and extracted once with 150 ml. of water and four times with 100 ml. of a saturated sodium bicarbonate solution. The toluene solution is then dried over magnesium sulfate and the solvent is removed in vacuo. Upon distillation of the residue, 3-benzyl-5-chloromethyl-1,2,4-oxadiazole, 19.8 g. having a b.p. of 100-108 (0.04 mm) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[C:6]([O-:8])=[O:7].N[C:27]1C=C2C(=CC=1)NC=C2CC1C=CC(C(OC)=O)=CC=1OC>O1CCCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:25])[CH:14]=[C:13]2[CH2:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)[O-])ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Yield: 98 %

Procedure:
A solution of (E) (0.56 g.) in tetrahydrofuran (30 ml.) was hydrogenated in the presence of palladium-on-carbon (10% w/w: 0.1 g.), as described for the amino ester (A) in Example 1, to give methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.50 g., 98%) as pale yellow foam: NMR: 3.6(s, H, NCH3), 3.8(s,3H, CO.OCH3), 3.9(br s,5H, OCH3 and CH2.Ar), 4.45(br,2H, NH2), 6.54(m,2H), 6.86(s,1H), 7.04(m,2H), 7.40(m,2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:38][C:34]1[CH:33]=[C:32]([N:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:31][CH2:30]2)[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
In the matter given in Example 1C, 4-chloro-7-(trifluoromethyl)quinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine to give 1-(m-chlorophenyl)-4-[[4-[[7-(trifluoromethyl)4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:21][CH2:22]1
Reactant: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ncc(-c2ccnc(Nc3ccc(OC)nc3)n2)c(CC2CC2)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
To a solution of 6-methoxypyridin-3-amine (61.4 mg, 0.494 mmol) in THF (5 mL) cooled to −78° C., lithium bis(trimethylsilyl)amide (1M in THF, 0.494 mL, 0.494 mmol) was added dropwise under nitrogen. After the reaction was stirred at −78° C. for 10 minutes, a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (30 mg, 0.099 mmol) in THF (1 mL) was added to the reaction at −78° C. The reaction was slowly warmed up to rt, then the reaction was allowed to stir for 1 hour. The reaction was quenched with saturated ammonium chloride solution, then concentrated in vacuo. The reaction was taken up in acetonitrile, purified by reverse-phase HPLC [10-90% organic phase over 15 minutes], then further purified by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM] to afford the title compound as a white solid (19.49 mg, 46.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.04 (br. s., 2H) 0.34 (d, J=7.58 Hz, 2H) 1.01 (br. s., 1H) 2.77 (d, J=6.57 Hz, 2H) 2.86 (d, J=4.55 Hz, 3H) 3.74-3.86 (m, 3H) 6.78 (d, J=9.09 Hz, 1H) 6.97 (d, J=5.05 Hz, 1H) 7.36 (d, J=4.04 Hz, 1H) 7.99 (dd, J=8.59, 2.53 Hz, 1H) 8.35-8.50 (m, 3H) 9.46 (s, 1H). HRMS (ES+) for C19H21N7O.H+ [MH+]: calcd, 364.1886; found, 364.1891. UV-LC: 94.60/100% UV purity at 254/214 nm; tR=5.08 minutes over 7.75 minutes.
Reaction SMILES: C([Mg]Cl)(C)C.[Li]CCCC.Br[C:12]1[C:13]([CH3:20])=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.[CH:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[CH3:19][O:18][C:15]1[N:16]=[CH:17][C:12]([CH:21]([OH:24])[CH2:22][CH3:23])=[C:13]([CH3:20])[CH:14]=1
Reactant: COc1cc(C)c(Br)cn1
Reactant: CCC=O
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1cnc(OC)cc1C
Reaction time: 0.25 h

Procedure:
To a cooled (−10° C.) solution of iPrMgCl (2.0M in THF, 619 ul, 1.24 mmol, 0.5 eq) in THF (5 ml) at is added n-BuLi (2.5M in hexanes, 990 ul, 2.47 mmol, 1 eq) and the mixture stirred at this temperature for 15 mins. This mixture is treated with a solution of 5-bromo-2-methoxy-4-methyl-pyridine (500 mg, 2.47 mmol) in THF (5 ml) and allowed to stir at −10° C. for 30 mins. After this time, propionaldehyde (0.324 ml, 4.45 mmol, 1.8 eq) is added and the contents left stirring for 2 hrs. The reaction is quenched with acetic acid (500 ul). The mixture is partitioned between EtOAc (100 ml) and Na2CO3 (2M, 50 ml) and the organic layer is separated, washed successively with 2M Na2CO3, water and brine, dried over MgSO4, filtered, and evaporated to yield the title compound as a clear oil. The crude 1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-ol is used without further purification. MS: m/z 182.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].[NH2:13][NH2:14]>C(O)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:13][NH:14][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: NN
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(O)cccc12
Reaction time: 72 h

Procedure:
3-Hydroxyphthalic anhydride (2.0 g, 12.2 mmol, Aldrich) was stirred with 25 mL of glacial acetic acid until nearly all dissolved. Hydrazine (8.4 mL, 268 mmol) was added dropwise to the mixture. The reaction mixture fumed and became homogeneous with development of a yellow color. After a few minutes, a white precipitate formed and the yellow color faded. The mixture was stirred for three days and then filtered. The solids were washed with 150 mL of water followed by 125 mL of acetonitrile and allowed to dry in the air and then under vacuum. Yield: 2.06 g (95%). 1H NMR (DMSO-d6): δ 12.83 (s, 1H), 12.06 (s, 1H), 11.68 (s, 1H), 7.76-7.70 (t, 1H), 7.34-7.31 (d, 1H), 7.14-7.12 (d, 1H); 13C NMR (DMSO-d6): δ 163.04, 160.68, 152.74, 136.37, 126.38, 118.34, 114.50, 113.76; MS: (m/e) 178 (M+), 148, 120, 92.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)([CH3:3])[CH3:2].[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CC(N)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:19])=[N:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (2.6 mL, 15 mmol) was added to a mixture of 5-chloropyrazine-2-carboxylic acid (0.80 g, 5.0 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.46 g, 5.56 mmol) and 2-propanamine (0.47 mL, 5.6 mmol) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with sat. aqueous NaHCO3, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS cacld. for C8H11ClN3O (M+1)+: m/z=200.1. Found: 200.1.
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([CH3:47])=[C:7]([CH:21]([N:23]([C:27]3[CH:46]=[CH:45][C:30]([C:31](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:32])=[CH:29][CH:28]=3)[CH2:24][C:25]#[CH:26])[CH3:22])[CH:8]=2)[N:3]=1.[NH2:48][C@@H:49]([CH2:54][CH2:55][C:56]1[NH:60][N:59]=[N:58][N:57]=1)[C:50]([O:52]C)=[O:51].C(OC)(=O)CCC>>[CH3:1][C:2]1[NH:11][C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]([CH3:47])=[C:7]([CH:21]([N:23]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([NH:48][CH:49]([CH2:54][CH2:55][C:56]4[NH:60][N:59]=[N:58][N:57]=4)[C:50]([OH:52])=[O:51])=[O:32])=[CH:45][CH:46]=3)[CH2:24][C:25]#[CH:26])[CH3:22])[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)C(C)c1cc2c(=O)n(COC(=O)C(C)(C)C)c(C)nc2cc1C
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
Solvent: CCCC(=O)OC
Product: C#CCN(c1ccc(C(=O)NC(CCc2nnn[nH]2)C(=O)O)cc1)C(C)c1cc2c(=O)[nH]c(C)nc2cc1C

Procedure:
Using analogous procedures to those described in Example 1 pentafluorophenyl p-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzoate was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate and the resultant methyl butyrate was hydrolysed to give 2- {p-{N-[1-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzamido}-4-(tetrazol-5-yl)butyric acid in 25% yields m.p. 207° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:15](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(O)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-hydroxy-4-nitro-phenyl)-acetamide (2 g, 10.15 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added potassium carbonate (2.6 g, 18.88 mmol) followed by methyl iodide (0.71 mL, 11.16 mmol) and the reaction mixture was stirred at room temperature for 1 hour. A second aliquot of methyl iodide (0.15 mL) was then added and the resulting mixture was stirred for 1 hour. Ethyl acetate (100 mL) and brine (100 mL) were added, the organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give N-(3-methoxy-4-nitro-phenyl)-acetamide.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccnc2)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 27.1 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 3-hydroxypyridine (3.00 g, 31.5 mmol) and 4-fluorobenzaldehyde (5.08 g, 41.0 mmol) was added potassium carbonate (8.71 g, 63.0 mmol) under nitrogen atmosphere, which was stirred for 17 hours at 70° C. The reaction mixture was then cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→3:1) to obtain the title compound (1.70 g, 27.1%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3F)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]>>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:5][CH2:4][C@@H:3]([NH:2][CH3:1])[CH3:6])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: CN[C@@H](C)CO
Product: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2S)-2-(methylamino)propan-1-ol (obtained as described in Chacchio et al., Tetrahedron, 1995, 51, 5689) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol in >100% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3H), 3.20 (m, 1H), 4.15 (dd, 1H), 4.30 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.70 (t, 1H), 8.00 (d, 1H), 8.50 (s, 1H); Mass spectrum MH+ 359.4.