Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.O.[CH3:22]N(C=O)C>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][NH:12][CH:22]=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)c2c[nH]nc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(Cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione (5 g) was dissolved in DMF (5 mL) followed by addition of POCl3 (4 mL) dropwise at 0° C. The reaction was warmed to 80 C. for 3 h, followed by stirring at RT overnight. The solution was added to 200 mL of water and filtered to give about 5 g of yellow solids. Proton NMR was sufficient to carry on to next step.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][OH:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:8][C:9]1[C:10]([CH2:20][CH2:21][CH3:22])=[CH:11][C:12]([CH:18]=[O:19])=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5.03 g (15.4 mmol)of t-butyl-dimethylsilyloxy-2,6-dipropyl-4-hydroxymethyl benzene in 30 mL of methylene chloride was added 8.7 g of pyridinium dichromate (PDC). The reaction mixture was stirred for 3 hours and then diluted with 300 mL of ethyl ether. The solution was then filtered through a pad of a 1:1 mixture of florisil and celite. Concentration of the tiltrate gave 4.85 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:29](Cl)([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31]>CN(C=O)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([O:17][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[C:9]([F:10])([F:11])[F:12]
Reactant: CC[Si](Cl)(CC)CC
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 10 g (38.6 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 100 mL of DMF was treated with 6.3 mL (42.4 mmol) of DBU and then dropwise with 6.5 mL (38.6 mmol) of TESCl. After stirring the mixture at RT overnight the solvent was partially evaporated i.v. Distribution of the crude mixture between a diluted aqueous solution of NaOH and Et2O and drying of the combined organic phases over Na2SO4 gave 13 g (90%) of 4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenylamine as a colorless oil, MS: 374 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=4)[C:23]#[N:24])[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: N#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-cyano-phenyl)-guanidine nitrate were converted to I-90 (58%): MS (AA) Rt═1.79 min, m/z═362 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:5]=1)[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:13][CH:14]=2)[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(O)cc2)n(-c2ccc(OC)cc2)n1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.7 %

Procedure:
To a solution of 4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol (515.5 mg) in DMF (5 ml) was added sodium hydride 60% dispersion in mineral oil (79.7 mg) at 3° C. The mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of tert-butyl (2-bromoethyl)carbamate (558 mg) in DMF (2 ml). The mixture was stirred at 60° C. for 24 hours. The reaction mixture was poured into ice water and was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from AcOEt, collected and washed with IPE to give 1st crop of tert-butyl (2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate (344 mg) as a white powder. The mother liqour was concentrated in vacuo and purified by silica gel column chromatography eluted with AcOEt/CHCl3=10% to give 2nd crop of tert-butyl (2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate (218 mg ) as a powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:28]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][N:22]=1)=[O:29]
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 98 %

Procedure:
The product L-phenylalanine methyl ester hydrochloride of Preparation example 1 (1.12 g, 5.2 mmol) was dissolved in 20 ml of THF, and neutralized with N-methyl morpholine (NMM) (0.7 ml, 6.2 mmol), then cooled with an ice bath for later use. Pyrazinecarboxylic acid (0.65 g, 5.2 mmol) was added to another reaction flask, dissolved with 20 ml of THF, cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) and HOBt (0.84 g, 6.2 mmol) were added at 0° C. and reacted for 40 min at 0° C., to which the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble N,N′-dicyclohexylurea (DCU) was removed by filtration, to the filtrate was added 150 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.37 g of white solid was obtained with a yield of 98%, m.p.: 152-155° C. 1H-NMR (CDCl3, 300 MHz): δ 3.26 (—CH2, m, 2H), 3.75 (—CH3, s, 3H), 5.09 (—CH, m, 1H), 7.15˜7.32 (-Ph, m, 5H), 8.23 (—CONH, d, 1H), 8.52 (-Pyz, d, 1H), 8.74 (-Pyz, d, 1H), 9.37 (-Pyz, s, 1H).
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])#[N:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C1C=CC=CC=1>C(N(CC)CC)C>[CH3:18][S:19]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyano-2 -(2,4-dichlorophenyl)hexan-1ol (5.6g., 0.02 mole) and methane sulfonyl chloride (2.9g., 0.025 mole) in 200 ml. of benzene is added dropwise at 10° C., 2.8g. (0.027) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 6.3g. of product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2c(Cl)c([N+](=O)[O-])ccc2[nH]1
Reaction time: 1 h

Procedure:
A solution of the above quinazolinedione (0.98 g, 5.0 mmol) in conc. H2SO4 (5 mL) was cooled to −10° C., and 90% HNO3 (0.35 g, 5.0 mmol) was added with stirring. Stirring continued for 1 h at −10° C., and 1.5 h at room temperature. The mixture was poured onto ice, filtered, washed with water and dried to give 5-chloro-6-nitroquinazolin-2,4-dione, along with some of the 8-nitro isomer (1.3 g, 94%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:30][CH2:31]Br)(=[O:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:31][O:30][C:27](=[O:29])[CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(=O)OCBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 146 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 0.047 ml of bromomethyl acetate. NMR (CDCl3) δ: 1.21 (3H, d, J=7.3 Hz), 1.35 (3H, d, J=6.3 Hz), 1.83 (1H, d, J=4.8 Hz), 2.14 (3H, s), 2.50 (1H, t, J=5.9 Hz), 3.29 (1H, dd, J1=6.8 Hz, J2=2.8 Hz), 3.51-3.61 (1H, m), 4.22-4.31 (2H, m), 4.86 (2H, d, J=5.9 Hz), 5.89 (1H, d, J=5.6 Hz), 5.97 (1H, d, J=5.6 Hz), 6.52 (1H, d, J=10.5 Hz), 7.13 (1H, d, J=10.5 Hz), 8.79 (1H, s)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]=O)=[C:5]([CH3:11])[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].BrBr.C(O[CH2:22][CH3:23])(=O)C>C(Cl)(Cl)Cl.ClCCl>[CH2:13]1[C:22]2[C:23](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH:12]1[N:4]1[CH:9]=[C:6]2[C:5]([N:4]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:15])[N:2]([CH3:1])[C:7]2=[O:8])=[CH:11]1
Reactant: CCOC(C)=O
Reactant: Cc1c(C=O)c(=O)n(C)c(=O)n1C(C)C
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C)c(=O)c2cn(C3Cc4ccccc4C3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,6-Dimethyl-5-formyl-1-(1-methylethyl)pyrimidine-2,4-dione (J. Med. Chem., 1995, 38, 2557, 1.70 g) was dissolved in chloroform (25 ml) and the solution was heated to 50° C. A solution of bromine (0.413 ml) in chloroform (20 ml) was added dropwise to the aldehyde solution over 24 minutes. The reaction was maintained at 50° C. for a further 15 minutes, then allowed to cool to ambient temperature. The reaction mixture was diluted with dichloromethane and was washed successively with water, dilute sodium thiosulphate solution (twice) and brine. The resultant solution was dried, filtered and evaporated to a crude oil which was dissolved in ethanol (50 ml). Triethylamine (3.38 ml) was added to the solution followed by 2-aminoindane (1.49 g) and the mixture was stirred under nitrogen overnight. The reaction mixture was filtered, the white solid collected was washed with a little ethanol and the filtrate was evaporated to give a brown oil. Ethyl acetate was added to the oil and the resultant precipitate was collected by filtration and was washed with a little ethyl acetate. The filtrate was washed with hydrochloric acid (HCl) (2.5 M) and then brine. The resultant ethyl acetate phase was dried, filtered and evaporated to an oil. The oil was purified by chromatography, eluting with isohexane:acetone (4:1) to give a solid which was triturated with hot ethyl acetate:isohexane (3:1) to give the subtitle compound (0.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)c1cccnc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cccnc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and nicotinic acid to yield (3aR,4S,7aR)-methyl 4-(nicotinoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=419; RT=3.553 min; HPLC Method III
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:20]([O:22][CH3:23])=[O:21])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([N+:17]([O-])=O)[CH:7]=4)[C:4]=2[CH:3]=1>C(O)C>[NH2:17][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]3[CH2:16][C:5]([C:20]([O:22][CH3:23])=[O:21])([C:4]4[C:13]3=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=4)[C:6]=2[CH:7]=1
Reactant: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc([N+](=O)[O-])cc12
Solvent: CCO
Product: COC(=O)C12CC(c3ccc(N)cc31)c1ccc(Cl)cc12
Temperature: 0 °C
Yield: 75.6 %

Procedure:
To a suspension of methyl 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 35b) (7.36 g, 22.32 mmol) in ethanol (150 mL) was added stannous chloride dihydrate (25.2 g, 112 mmol, 5 eq). The reaction was heated to reflux at which time it became homogeneous. After heating for 2.5 h, the solution was cooled to 0° C. and quenched with ice followed by 10% NaOH (200 mL). The aqueous phase was extracted with ethyl acetate (3×150 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a solid. The reaction product was purified by flash chromatography over silica gel (400 mL, eluent: 25% ethyl acetate in hexane) to yield 5.06 g (76%) of the title compound. TLC analysis (Rf 0.16, 30% ethyl acetate in hexane). MS (CI, CH4) m/z 300 (M+1,100), 302 (33), 328 (M+29,9), 264 (12), 182 (11), 121 (11), 89 (44).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH3:15])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 20.9 g of 2-(4-nitrophenyl)butyric acid in 500 ml of dry tetrahydrofuran was added, dropwise, 1.1 equivalents of 10 M borane-dimethylsulfide complex in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 1.5 hours and then refluxed for 1.5 hours and finally cooled to room temperature. Methanol (10 ml) was added, the mixture was stirred for 30 minutes, and the solvent was then evaporated under reduced pressure. The residue was dissolved in 100 ml of methanol and the solvent was evaporated and this procedure was repeated three (3) times. The resulting oil was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane to give 2-(4-nitrophenyl)butanol as a light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[C:14]([N+:22]([O-])=O)[CH:13]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:19]([CH3:20])[NH:22][C:14]=2[CH:13]=1
Reactant: CC(=O)Nc1ccc(-c2nc3cc(C)ccn3c2C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccn2c(C)c(-c3ccc4nc(C)[nH]c4c3)nc2c1
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 3,7-dimethyl-2-(4-acetoamido-3-nitrophenyl)imidazo[1,2-a]pyridine (2 g) in methanol (200 ml) was hydrogenated over 10% palladium on carbon (wet, 400 mg) under an atmospheric pressure of hydrogen at ambient temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to 20 ml of volume and allowed to stand overnight. Th.e precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on aluminum oxide (50 g) eluting with chloroform. The fractions containing the object compound were combined and allowed to stand overnight. The resultant yellow needles were collected by filtration and dried under reduced pressure to afford 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-methylbenzimidazole (0.51 g). mp. 250°-253° C. (dec.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[C:15](OCC)=[O:16])=[CH:11][CH:10]=1>CCOCC>[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12](/[CH:13]=[C:14](\[CH2:20][CH3:21])/[CH2:15][OH:16])=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OC)cc1)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC/C(=C\c1ccc(OC)cc1)CO
Yield: 83.4 %

Procedure:
To a suspension of lithium aluminum hydride (3 g) in dry ether (300 ml) was added a solution of ethyl 2-((E)-4-methoxybenzylidene)butyrate (19 g) in dry ether (30 ml) at 0° C. with stirring. The mixture was stirred at the same temperature for 3 hours and excess lithium aluminum hydride was decomposed with wet ether. The reaction mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and then evaporated to dryness to give 2-((E)-4-methoxybenzylidene)butan-1-ol (13 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[CH:2]=1.[OH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:22])[CH:28]=4)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[CH:2]=1
Reactant: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Reactant: OB(O)c1cccc(O)c1
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3cccc(O)c3)cn2)C1
Yield: 47.2 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridin-3-ylamide (300 mg, 0.76 mmol) was reacted with 3-hydroxyphenylboronic acid (156 mg, 1.14 mmol) to afford a crude product purified by flash chromatography on silica gel eluting with solvent gradient of 1:19 to 1:9 7N ammonia in methanol solution: dichloromethane. This affords the title compound (130 mg, 47%) as a colourless powder.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>CO>[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][N:2]([CH3:3])[CH3:1]
Reactant: BrCc1ccccc1Br
Reactant: CNC
Solvent: CO
Product: CN(C)Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
Dimethylamine (33% w/w in methanol) (25 ml) was added to 2-bromobenzylbromide (7.5 g 30 mmol) at 0° C. in methanol (35 ml), and the solution stirred for 30 min., evaporated, diluted with water and extracted twice with diethyl ether. The combined extracts were dried over sodium sulphate and evaporated to give product as a yellow oil (6.0 g). M+ 215/213; 360 MHz 1H n.m.r (CDCl3) 7.54 (1H, dd, J 1.2, 8.0 Hz), 7.42 (1H, dd, J 1.6, 7.6 Hz), 7.30-7.26 (1H, m), 7.11 (1H, dt, J 1.7, 7.7 Hz), 3.52 (2H, s), 2.30 (6H, s).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Product: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 34 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound in 34% yield; NMR spectrum (DMSO-d6, 373K) 1.20 (d, 3H), 1.85 (s, 3H), 2.80 (s, 3H), 3.00 (m, 1H), 4.30 (m, 1H), 4.40 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (t, 1H), 7.80 (m, 1H), 7.90 (d, 1H), 8.40 (s, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MH+ 492.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:7]=2)=[CH:10][CH:11]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1ccc(Oc2cc(Cl)ncn2)cc1
Product: COc1cc(Nc2cc(Oc3ccc(Cl)cc3)ncn2)ccc1-n1cnc(C)c1
Temperature: 200 °C
Yield: 18 %

Procedure:
The title compound was prepared from 4-chloro-6-(4-chloro-phenoxy)-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine in analogous manner as described in example 62 by heating the reaction mixture in a microwave oven at 200° C. for 2.5 h. Obtained as a yellow solid in 18% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>CO>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:24]
Reactant: CNC
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3ccc(CN(C)C)cc3)oc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.72 mmol) in methanol (2 mL), was added dimethylamine solution (0.5 mL, 2.88 mmol), the resulting mixture was stirred at room temperature for 17 hr, then the solvents were evaporated and methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate. LC-MS (ESI) m/z 311 [M+1]+.