Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:31]CC1>O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][OH:31])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a solution of 5-vinyl-indole-1-carboxylic acid tert-butyl ester (4.5 g, 18.5 mmol, 1.0 eq.) in THF (46 mL) at 0° C. was added 9-BBN (0.5 M in THF, 87 mL, 2.4 eq.) over 10 min. The resulting reaction mixture was stirred for 2.5 h and diluted with THF (150 mL) and water (150 mL) while keeping the temperature at 0° C. Then NaBO3.4H2O (44 g) was introduced and resulting reaction mixture was stirred and warmed to room temperature and stirred. The reaction mixture was diluted with methylene chloride (100 mL) and the separated aqueous layer was extracted 3×100 mL methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (methylene chloride to 5% acetone/methylene chloride) to give 5-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester (3.82 g, 76%) or similarly 6-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[NH:25][C:24]4[C:23](=[O:26])[N:22]([CH:27]5[CH2:29][CH2:28]5)[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH3:33])[C:19]=4[N:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>N1C=CC=CC=1>[CH:27]1([N:22]2[C:23](=[O:26])[C:24]3[NH:25][C:17]([C:14]4[CH:13]=[CH:12][C:11]([N:10]([CH2:9][C:6]5[CH:7]=[N:8][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=5)[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[N:16][CH:15]=4)=[N:18][C:19]=3[N:20]([CH2:31][CH2:32][CH3:33])[C:21]2=[O:30])[CH2:28][CH2:29]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(NCc4ccc(C(F)(F)F)nc4)nc3)nc21
Solvent: c1ccncc1
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(N(Cc4ccc(C(F)(F)F)nc4)C(=O)C(C)(C)C)nc3)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-(6-((6-(trifluoromethyl)pyridin-3-yl)methylamino)pyridin-3-yl)-1-cyclopropyl-3-propyl-1H-purine-2,6(3H,7H)-dione (35 mg, 0.07 mmol) was dissolved in pyridine (5 ml) at 60° C. After cooling, pivaloyl chloride (100 mg, 0.83 mmol) was added. The mixture was stirred at room temperature for 24 h. After quenching with ice, the mixture was evaporated and purified by silica gel column to give product (4).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].O1CCCC1.C(O)(=O)C.[CH3:27][S:28][CH2:29][C:30](=O)[CH3:31]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[C:30]([CH3:31])[CH2:29][S:28][CH3:27])=[O:14])[CH3:2]
Reactant: CSCC(C)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=C(C)CSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a 200 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazine ((12-1)-(11)-39) (6.44 g), tetrahydrofuran (72 ml), and acetic acid (1.65 g) were added under a nitrogen atmosphere. 1-methylsulfanyl-2-propanone (7-0-1) (3.12 g) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (30 ml), and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 7.17 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(8)-39).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH:14](OCC)(OCC)OCC.C(=O)(O)[O-].[Na+]>>[F:11][C:9]([S:8][C:6]1[CH:5]=[CH:4][C:3]2[O:13][CH:14]=[N:1][C:2]=2[CH:7]=1)([F:12])[F:10]
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)Sc1ccc2ocnc2c1

Procedure:
A mixture of 0.50 g of 2-amino-4-trifluoromethylsulfanylphenol and 3 ml of triethyl orthoformate was stirred under heating and refluxing for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.50 g of 5-trifluoromethylsulfanylbenzoxazole.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]#N)=[CH:4][CH:3]=1.[OH2:18].S(=O)(=O)(O)[OH:20].Cl>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:20])=[O:18])=[CH:4][CH:3]=1
Reactant: O
Reactant: N#CCc1ccccc1Cc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccccc1Cc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 74 %

Procedure:
[2-(4-fluoro-benzyl)-phenyl]-acetonitrile is suspended in acetic acid (0.5 L/mol), water (0.3 L/mol) and sulphuric acid (0.35 L/mol). After 5 hours at reflux, the mixture is cooled down, water (1.2 L/mol) and dichloromethane (0.3 L/mol) are added. The organic extract is washed with water (1.3 L/mol) and sodium hydroxide 50% (0.15 L/mol). After stirring for 20 min., the aqueous layer is separated and washed with CH2Cl2 (0.1 L/mol) which is discarded. The aqueous layer is acidified with concentrated hydrochloric acid (2 eq.). The mixture is stirred during 3 hours, the precipitate is then filtered off and washed with water (0.1 L/mol). Yield: 74%.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([N:13]2[CH2:14][CH2:15][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:9][C:8]3=[O:10])[CH2:12]2)=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3ncc(Cl)cn3)C2)C(=O)O1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2,5-dichloropyrimidine at 150° C. for 20 min. LC-MS Method 1 tR=1.51 min, m/z=431,433(M+1); 1H NMR (CD3OD) 8.24(s, 2H), 7.41-7.27(m, 5H), 4.78(m, 1H), 3.71-3.57(m, 2H), 2.73(m, 1H), 2.52(m, 2H), 2.17(s, 2H), 1.24(s, 3H), 0.93(s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:36](O)=[O:37])[C:30]=2[CH:29]=[CH:28][N:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]=[CH:26]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2cnccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cnccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and isoquinoline-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[NH:11][C:10]1=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si:35]([O:42][CH2:43][CH2:44][C:45]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:48]([C:45]2([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:46][CH2:47]2)(=[O:50])=[O:49])[C:10]1=[O:24]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1ncnc2c(F)c3c(cc12)[nH]c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1(CCO[Si](C)(C)C(C)(C)C)CC1)c(=O)n3-c1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (example 34, step H) (90 mg, 0.22 mmol) in THF (5 ml) at −78° C. is added LiHMDS (0.29 ml, 1 M in THF, 0.29 mmol). The reaction mixture is stirred at −78° C. for 30 min and 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropane-1-sulfonyl chloride (99 mg, 0.33 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×30 ml). The combined organic solution is washed with brine (30 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: [Br:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[F:20].S(Cl)(Cl)=O>CN(C)C=O.C1CCCCC1>[Br:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([O:18][CH2:7][CH2:8][N:9]([CH3:14])[CH3:10])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[F:20]
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)OCCN(C)C)cn1c23

Procedure:
A mixture of 3.0 g of 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 25 ml of thionyl chloride and 2 drops of N,N-dimethylformamide was heated on a steam bath for 15 minutes. The excess thionyl chloride was removed by evaporation. The residue of solid 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxyl chloride was suspended in 100 ml of dichloromethane, the mixture was stirred and 10 ml of dimethylaminoethanol was added. After 10 minutes of stirring the solution was washed with sodium bicarbonate solution, then dried over magnesium sulfate. The solution was treated with decolorizing charcoal, filtered and concentrated to provide an oil. When cyclohexane was added, tan solid N,N-dimethylaminoethyl 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate formed. This product was dissolved in 50 ml of hot isopropanol, treated with decolorizing charcoal and filtered. A solution of isopropanol saturated with hydrogen chloride gas was added until the mixture became acidic. The white precipitate that formed was N,N-dimethylaminoethyl 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate hydrochloride, m.p. 250° C. (dec.) Analysis: Calculated for C18H20BrFN2O3.HCl: %C, 48.3; %H, 4.7; %N, 6.2; Found: %C, 48.4; %H, 5.0; %N, 6.2.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C.Cl>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)Cc1c(C)cc(C)cc1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (0.506 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 6.0 mL of a 1.6 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of (2,4,6-trimethyl-phenyl)-acetic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred 5 h at room temperature. Subsequently, the reaction mixture is acidified (pH 7–8) with dropwise addition of conc. HCl and a 1 M HCl(aq) solution. The quenched reaction mixture is then partitioned between water and ethyl acetate. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the desired 3-oxo-4-(2,4,6-trimethyl-phenyl)-butyronitrile as a yellow-white solid in the amount of 1.41 gms. (72% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To tert-butyl 4-[(tert-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (15.7 g; 50.1 mmol; 1 eq.) in water (78.5 mL) and glacial acetic acid (78.5 mL) is added sodium cyanoborohydride (3.15 g; 50.1 mmol; 1 eq.) and the reaction mixture is stirred at rt overnight. The solvents are removed to near dryness and the product is extracted with AcOEt. The combined organic phase is washed with NaOH (1 M), dried over MgSO4, filtered and concentrated to afford: 14.1 g (89%) of the title compound. 1H NMR (300 MHz, DMSO): δ 8.22 (s, 1H), 4.61-4.14 (m, 1H), 3.81-3.55 (m, 2H), 3.08-2.67 (m, 2H), 1.73-1.50 (m, 2H), 1.38 (s, 18H), 1.22-0.98 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[B:11]([OH:13])O)=O.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[NH:26][NH2:27])=[CH:17][CH:16]=1.NN>C(O)C.CC(O)=O>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]=[C:21]2[N:26]2[N:27]=[CH:1][C:3]3[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=3[B:11]2[OH:13])=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: NNC1=NCC(=O)N1Cc1ccc(Cl)cc1
Agent: NN
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)C=NN(C1=NCC(=O)N1Cc1ccc(Cl)cc1)B2O

Procedure:
A mixture of 1 (360 mg, 2.0 mmol) and 3-(4-chlorobenzyl)-2-hydrazino-3,5-dihydroimidazol-4-one (compound 16, commercially available from Maybridge Chemical Co., Ltd., Ryan Scientific #RF03409; 500 mg, 2.1 mmol) in 6 mL of absolute ethanol was treated with 1 drop of AcOH and was warmed on a steam bath until homogeneous. The mixture was allowed to stand at 23 ° C. overnight, whereupon the 137 mg of the starting hydrazine that had separated as crystals (mp 186-188° C.) was removed by suction filtration. The filtrate was rotary evaporated to dryness, and the residue was triturated with Et2O to give 528 mg (69%, 91% based on unrecovered hydrazine) of the methoxy precursor (compound 17) as a pale yellow powder: mp 135-145° C. (EtOH). 1H NMR ((CD3)2SO) δ 9.16 (s, exchanges with D2O, 1, OH), 7.62 (d, J=8.4 Hz, 1), 7.40 (d, J =8.5 Hz, 2, p-CICA), 7.32 (d, J=8.5 Hz, 2, p-ClC6H4), 7.12 (m, 3), 6.97 (d, J=8.0 Hz, 1), 6.85 (d, J =8.0 Hz, 1), 6.68 (s, 1), 4.23 (d, J=5.6 Hz, 2, benzyl-CH2), 3.67 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 383 (2%, MH+). Deprotection of 17 can be effected using conventional techniques to form 18.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.[F:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1.ClCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][F:29])[CH2:37][CH2:36]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCCN1CCN(CCF)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Diisopropylazodicarboxylate (921 mg, 4.56 mmol) was added portionwise, at room temperature, to a stirred suspension of 4-chloro-6-methoxyquinazolin-7-ol (800 mg, 3.80 mmol), 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (794 mg, 4.18 mmol) and triphenylphosphine (1.4 g, 5.34 mmol) in THF (20 ml). The reaction was stirred 1 hr. before adding triphenylphosphine (1.4 g), di-tert-butylazodicarboxylate (1.05 g, 4.56 mmol) and dichloromethane (10 ml). The reaction was stirred for a further 1 hr. then evaporated and purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent then on alumina (neutral) using 10% methanol in dichloromethane as eluent to give 4chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (696 mg, 48%) as a colourless solid; NMR Spectrum:(CDCl3) 2.13 (quintet, 2H), 2.55 (m, 10H), 2.67 & 2.76 (dt, 2), 4.06 (s, 3H), 4.30 (t, 2H), 4.53 & 4.64 (dt, 2H), 7.36 (s, 1H), 7.38 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:19]([O:18][CH3:17])[CH:20]=[CH:21][C:22]=3[O:25][CH3:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CNC(=O)c1nnc2c(Br)cccc2c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N
Yield: 59.2 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-methyl-cinnoline-3-carboxamide (20.0 g, 63.1 mmol) and 2,5-dimethoxyphenyl boronic acid (22.3 g, 122.4 mmol) according to Method B except that potassium carbonate was used as the base and tetrahydrofuran:ethanol:water (1:1:1) was used as the solvent system. The reaction mixture was filtered and the yellow solids were slurried in 10% methanol in chloroform and filtered. The combined filtrates were concentrated to a solid, slurried in hot ethyl acetate, and filtered. The combined solids were further purified on silica gel using 5% methanol in chloroform as the eluent. A final crystallization from refluxing ethyl acetate followed by drying under high vacuum at 45° C. afforded the title compound as a light yellow solid (12.65 g, 59%). 1H NMR (500.333 MHz, DMSO) δ 9.07 (d, J=4.6 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.03 (d, J=9.1 Hz, 1H), 6.97 (dd, J=8.9, 3.0 Hz, 1H), 6.87 (d, J=3.2 Hz, 1H), 3.73 (s, 3H), 3.55 (s, 3H), 2.86 (d, J=4.8 Hz, 3H). MS APCI, m/z=xx (M+H). HPLC 2.23 min. MP=279.1-279.8.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 2.76 g (18 mmol) of 3,6-dichloropyridazine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3.5 h at 80° C., diluted with 1 ml DMF and heated for 4 days at 80° C. and one day at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 95:5 to 9:1) gave 0.61 g (54%) of trans-3-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 280 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a yellow solid (0.44 g, 51% yield), mp=68–71° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=+22.8° (c=1, EtOH).