Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:36]([C:35]1[CH:38]=[CH:39][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:33][CH:34]=1)=[O:37]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Yield: 67.5 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (3.0 g; 7.05 mmol) in 8 ml of DMF was treated with 6-chloronicotinaldehyde (0.91 g; 6.42 mmol) and K2CO3 (0.97 g; 7.05 mmol). The reaction mixture was heated at 150C for 4 hr. Upon cooling, the mixture was partitioned between ethyl acetate and 0.05N HCl. The organic phase was washed with 0.05N HCl and brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using ethyl acetate-hexane mixtures (5–50%) afforded the title compound (2.3 g; 68% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CN
Reactant: ClCc1cccc2ccccc12
Solvent: CCO
Product: CNCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
17.6 g of 1-chloromethyl-naphthalene in 40 ml of absolute ethanol is added, dropwise, at 0° to 5°, to 100 ml of a 33% solution of methylamine in absolute ethanol. The mixture is allowed to stand overnight and is then evaporated. The residue is taken up in a little chloroform and washed with 100 ml of 1 N sodium hydroxide solution and with water. The organic phase is dried and evaporated to dryness. The residue is distilled at 0.01 Torr to obtain the heading compound as main fraction, b.p. 85°-87°.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:9]([N:11](CC)CC)[CH3:10].C1(N=C=[O:24])C=CC=CC=1.[N+](CC)([O-])=O>C1(C)C=CC=CC=1>[CH3:10][C:9]1[CH:2]2[C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH:1]2[O:8][N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1C=CCCCC1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC[N+](=O)[O-]
Product: CC1=NOC2CCCCC(=O)C12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 80% technical grade 2-cycloheptenone (3.48 mL, 25 mmol) and triethylamine (1 mL) in toluene were added phenylisocyanate (5.95 g, 50 mmol) and nitroethane (2.24 g, 30 mmol) in four portions over 1 hour. The reaction mixture was stirred at ambient temperature for 4 hours, the precipitate was filtered off and the filtrate was concentrated. The obtained residue was chromatographed, eluting with 20% ethyl acetate/hexane to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 4.81 (m, 1 H), 4.06 (d, J=11.87 Hz, 1 H), 2.47 (m, 2 H), 2.02 (m, 3 H), 1.93 (m, 2 H), 1.81 (m, 2 H), 1.67 (m, 2 H); MS (DCI/NH3) m/z 168 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][CH:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:3]1[CH:4]=[CH:5][C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][CH:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[CH:7][C:2]=1[F:1])#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 2′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) was added dropwise ethyl diazoacetate (0.52 mL) at 100° C., and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.33 g, 58%).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:41]/[O:42][CH3:43])/[C:12]([NH:14][C@@H:15]2[C:25](=[O:26])[N:24]3[C@@H:16]2[S:17][CH2:18][C@H:19]2[C@:23]3([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[O:22][C:21](=[O:40])[CH2:20]2)=[O:13])[N:10]=1)=O.CNC(=S)[S-].[Na+].C(OCC)(=O)C>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:41]/[O:42][CH3:43])/[C:12]([NH:14][C@@H:15]2[C:25](=[O:26])[N:24]3[C@@H:16]2[S:17][CH2:18][C@H:19]2[C@:23]3([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:28])[O:22][C:21](=[O:40])[CH2:20]2)=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@H]1CC(=O)O[C@@]12C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@H]1CC(=O)O[C@@]12C(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
In 5 ml of anhydrous N,N-dimethylformamide was dissolved 0.334 g of the compound obtained in Example 16, to which was added 0.132 g of sodium N-methyldithiocarbamate, folowed by stirring at room temperature for 1.5 hour. To the reaction mixture was added 30 ml of ethyl acetate, which was washed with water and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate-chloroform-methanol (15:15:1). Fractions containing the end product were combined and concentrated under reduced pressure to give 0.206 g of the subject compound as powders.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:39])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:39][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: COc1ccc(O)cc1OC
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC)c(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3,4-dimethoxyphenol (0.42 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.57 g, 61%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]([C:18]([NH:20][C@H:21]([C@H:29]([OH:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16].N=[C:50]=[NH:51]>>[NH:51]1[C:50]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C@H:29]([OH:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:44])[CH3:45])[NH:42][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: N=C=N
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)C

Procedure:
Indole-2-carboxylic acid was coupled to the resultant compound of Example 317 using the carbodiimide coupling procedure of Example 55 to provide the desired compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:21](=[O:22])[N:20]([CH3:24])[CH3:19])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N,N-dimethylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N,N-dimethylcarbamoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added isocyanatobenzene (19 mg, 0.16 mmol) at ambient temperature drop-wise. The reaction was stirred for 5 minutes then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (30 mg, 87% yield). MS (apci) m/z=435.2 (M+H).
Reaction SMILES: [F-].[K+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[C:7]([OH:8])[CH:6]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].O>CS(C)=O>[N+:25]([C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[O:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][C:9]=1[O:10][CH3:11])[CH:4]=[O:3])([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: COc1ccc(C=O)cc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)cc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a stirred suspension of potassium fluoride (457 mg, 7.8 mmol) in dry DMSO (20 ml) was added a solution of isovanillin (1.0 gm, 6.57 mmol) in dry DMSO (20 ml). The reaction contents were heated at 140° C. for 10 min. A solution of 4-fluoro-3-nitrobenzotrifluoride (1.37 gm, 6.57 mmol) in dry DMSO (10 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4.0 h. The reaction mixture was cooled to room temperature and the contents were poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (50 ml×2), water and brine and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo to obtain 3-(2-nitro-4-trifluoromethyl phenoxy)-4-methoxy benzaldehyde as a pale yellow solid (2.0 gm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:9]([C:11]1[C:12](=[O:21])[N:13]([CH2:19][CH3:20])[N:14]=[CH:15][C:16]=1C#N)#[N:10]>C(O)C>[C:9]([C:11]1[C:12](=[O:21])[N:13]([CH2:19][CH3:20])[N:14]=[CH:15][C:16]=1[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)#[N:10]
Reactant: NCc1ccncc1
Reactant: CCn1ncc(C#N)c(C#N)c1=O
Solvent: CCO
Product: CCn1ncc(NCc2ccncc2)c(C#N)c1=O
Yield: 14.6 %

Procedure:
Into 305 ml of an absolute ethanol solution of 1.9 g of 4-picolylamine, 30 ml of an absolute ethanol suspension of 1.4 g of 4,5-dicyano-2-ethylpyridazin-3-(2H)-one was dropwise added under cooling with ice over a period of 30 minutes. After completion of the dropwise addition, the mixture was reacted at room temperature overnight. Then, ethanol was distilled off under reduced pressure. To the residue, 250 ml of ethyl acetate and 100 ml of water were added, followed by shaking. The ethyl acetate layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography, and using an eluent (ethyl acetate:methanol=40:1), 0.3 g of the desired product (Compound No. 47) was obtained.
Reaction SMILES: [Br-:1].[Na+].[CH3:3][C:4]1[C:5](=[O:21])[O:6][C:7]([CH2:15]OS(C)(=O)=O)=[C:8]([CH3:14])[C:9]=1[O:10][CH2:11][O:12][CH3:13]>CN(C=O)C>[Br:1][CH2:15][C:7]1[O:6][C:5](=[O:21])[C:4]([CH3:3])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:8]=1[CH3:14]
Reactant: [Br-]
Reactant: COCOc1c(C)c(COS(C)(=O)=O)oc(=O)c1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)c(CBr)oc(=O)c1C
Reaction time: 1 h

Procedure:
Sodium bromide (500 mg) was added to a solution of 3,5-dimethyl-4-methoxymethoxy-6-(methylsulfonyloxy)methyl-2H-pyran-2-one (1.35 g) in DMF (20 ml), and after the stirring the mixture at room temperature for one hour, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H](OC)[CH2:4][C@@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.[ClH:27].CO.CC(C)=O>CO>[ClH:27].[OH:1][C@@H:2]1[CH2:6][O:7][CH2:4][C@H:3]1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[N:12]=1
Reactant: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12

Procedure:
4-[(3R,4R)-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline 1/2 hydrochloride (cf. Example 21) (178 mg) is dissolved in methanol (3 ml) with heating, and thereto is added 2N HCl-methanol (0.32 ml) and acetone (10 ml), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(3R,4R)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline monohydrochloride (124 mg) as crystals.
Reaction SMILES: C([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH:25][C:26](=[O:39])/[C:27](/[CH3:38])=[CH:28]/[C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:9]1)=[O:7])(C)(C)C.[ClH:49].C(OCC)C>FC(F)(F)C(O)=O.ClCCl>[ClH:49].[CH:43]1([CH2:42][O:41][C@@H:10]2[O:11][CH2:12][C@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH:25][C:26](=[O:39])/[C:27](/[CH3:38])=[CH:28]/[C:29](=[O:37])[N:30]([CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH3:36])[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[N:8]([C:6]([OH:7])=[O:5])[CH2:9]2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2CCCCC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2CCCCC2)CN1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Dissolve (2R,5R)-2-cyclohexylmethoxy-5-[(1S,2S)-3-(3,5-difluorophenyl)-2-((E)-3-dipropylcarbamoyl-2-methylacryloylamino)-1-hydroxypropyl]-morpholine-4-carboxylic acid tert-butyl ester (0.051 g, 0.075 mmol) in trifluoroacetic acid (1.5 mL) and stir at room temperature for 15 minutes. Dilute with dichloromethane (15 mL), concentrate, dissolve in ethyl acetate (30 mL), wash with 1:1 saturated aqueous sodium chloride:saturated aqueous sodium bicarbonate (30 mL), dry (sodium sulfate) and concentrate. Dissolve the residue in ethyl acetate and add 1 M hydrogen chloride in diethyl ether (0.20 mL, 0.20 mmol) and concentrate to give the title compound (0.045 g, 97.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]=[O:15].[Cl-].C[Al+]C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]([CH2:14][OH:15])[CH2:12][O:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Brc1cccc(C2=CCOCC2)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: OCC1COCC=C1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A 0° C. solution of 4-(3-bromophenyl)-3,6-dihydro-2H-pyran (0.50 g, 2.09 mmol) in CH2Cl2 (15 mL) is treated with paraformaldehyde (0.208 g, 2.20 mmol) and stirred for 5 minutes at 0° C. A 1 M solution of dimethylaluminum chloride in hexanes (3.03 mL, 3.03 mmol) is added drop-wise to the slurry. The reaction is warmed to room temperature and stirred for 1 hour. The reaction is cooled to 0° C. and more paraformaldehyde (0.208 g, 2.20 mmol) and 1 M solution of dimethylaluminum chloride in hexanes (3.03 mL, 3.03 mmol) is added. The reaction is warmed to room temperature and stirred overnight. The reaction is quenched by pouring into an ice/1 N HCl mixture and is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified on silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.315 g, 53%). 1H NMR (400 MHz, CDCl3) δ 7.50 (t, J=2.0 Hz, 1H), 7.40 (dd, J=2.2, 7.9 Hz, 1H), 7.29-7.27 (m, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.11 (t, J=2.9 Hz, 1H), 4.32-4.29 (m, 2H), 4.28-4.25 (m, 1H), 3.76 (dd, J=3.1, 11.4 Hz, 1H), 3.70-3.64 (m, 2H), 2.70 (d, J=2.2 Hz, 1H), 1.89 (dd, J=4.6, 6.4 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH2:32])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:18]=[C:17]([CH3:29])[N:16]=2.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH:32][C:2](=[O:3])[O:4][CH3:5])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[N:18]=[C:17]([CH3:29])[N:16]=2
Reactant: COC(=O)Cl
Reactant: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCN)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCCn1c(-c2ccccc2Cl)nc2c(N3CCN(C)CC3)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Add methyl chloroformate (0.25 g, 0.0027 mol) to a solution of 2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethanamine (0.39 g, 0.0010 mol) and pyridine (4.0 mL) in dry dichloromethane (4 mL) at 0° C. Allow to warm to room temperature and stir for 2 hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (97:3) as eluent to afford methyl N-[2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethyl]carbamate (0.3 g). ES/MS m/z 444 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:16][C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:10][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14]
Reactant: COc1cc(NC(=O)C(C)C)ccc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of N-(3-methoxy-4-methyl-phenyl)-isobutyramide (5.0 g, 24.1 mmol) in dichloromethane (200 mL) was added tetrabutylammonium tribromide (12.2 g, 25.3 mmol) at 0° C. The mixture was then stirred at room temperature for 20 hours. The solution was washed with water, brine, aqueous sodium bicarbonate solution, brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.83 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.29 (d, J=7.03 Hz, 6 H), 2.15 (s, 3 H), 2.59 (m, 1 H), 3.84 (s, 1 H), 7.24 (s, 1 H), 7.65 (bs, 1 H), 8.08 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:18][CH:17]=[C:16]([F:30])[C:13]=1[CH:14]=[O:15].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:14]([C:13]3[C:16]([F:30])=[CH:17][CH:18]=[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:12]=3[F:11])[OH:15])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(F)ccc(OCCOC2CCCCO2)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 118 mg, 0.000597 mol) in methanol (9.0 mL) were added 2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541, 180.0 mg, 0.63 mmol) and potassium hydroxide (601.9 mg, 10.7 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound that was used directly in the next step.