Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[Na+].[Na+].CC(C)([O-])C.[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)C>[CH2:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:14]1[O:16][CH2:15]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
Into a reaction vessel were put phthalimide (2.00 g, 13.6 mol), (R)-epichlorohydrin (2.26 g, 24.5 mmol), anhydrous sodium carbonate (0.72 g, 6.80 mmol), tetra n-butylammonium hydrogensulfate (0.46 g, 1.36 mol) and isopropanol (13 ml) and the mixture was reacted at room temperature at 50° C. for 23 hours. And then to the residue was gradually added potassium tert-butoxide (1.83 g, 16.3 mmol) in isopropanol and the mixture is stirred at 20° C. for 1 hour. After the reaction, post-treatment was carried out to give crude (R)-glycidylphthalimide (2.21 g, yield 80%, optical purity 98% e.e.) as white crystals.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.N1C=CN=C1>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1
Reactant: CCOC(=O)[C@H](C)Nc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 22 %

Procedure:
A solution of ethyl N-phenylalaninate (9.65 g, 50 mmol) and 2,4-dichloro-5-nitropyrimidine (9.7 g, 50 mmol) in anhydrous dichloromethane (100 mL) was stirred for 5 minutes at rt under nitrogen. The solution was then cooled to 0° C. (Ice bath) followed by addition of imidazole (3.41 g, 50 mmol). The resulting reaction mixture was allowed to warm up to rt in 30 min and further heated at 50° C. for 2 h. The reaction was then cooled to rt, washed with water, dried over sodium sulfate and evaporated to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (5:95)) to afford desired product (22%). 1HNMR (300 MHz, CDCl3): δ 1.29 (t, J=7.2 Hz, 3H), 1.63 (d, J=7.5 Hz, 3H), 4.18-4.27 (m, 2H), 4.90 (q, J=7.2 Hz, 1H), 7.19 (d, J=6.9 Hz, 2H), 7.26-7.39 (m, 3H) and 8.52 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[OH:8][CH2:9][C:10]([N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:13])=[O:11]>>[OH:8][CH2:9][C:10]([N:12]([CH3:13])[CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[S:4][CH:5]=[CH:6][N:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)=[O:11]
Reactant: ClCc1nccs1
Reactant: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1OCc1nccs1
Yield: 38 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 3, preparation of starting materials) to give the title compound as a white solid in 38% yield; NMR spectrum (DMSO-d6 373K) 2.27 (s, 3H), 2.98 (s, 3H), 3.91 (t, 2H), 4.07 (s, 2H), 4.47 (t, 2H), 5.44 (s, 2H), 7.09 (d, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.54 (m, 2H), 7.67 (t, 1H), 7.70 (d, 1H), 7.83 (d, 1H), 8.41 (s, 1H), 9.63 (s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(OC([N:18]1[C:26]2[N:21]([C:22](=[O:28])[N:23]=[C:24](Cl)[CH:25]=2)[CH2:20][C@@H:19]1[CH3:29])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:10][C:24]1[CH:25]=[C:26]2[NH:18][C@@H:19]([CH3:29])[CH2:20][N:21]2[C:22](=[O:28])[N:23]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1cc(F)cc(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)cc(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluorophenyl)methanol and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14].O>CO>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Racemic cis-1-amino-2-indanol (66.6 g, water wet, content 81.1%) and 65 g of (R,R)-tartaric acid in 360 ml of methanol with 20 ml of water were brought to reflux. Stirring of the mixture was continued for one hour at reflux and then it was cooled down again to 20° C. The solid was isolated by filtration and washed twice with 120 ml of methanol. After drying, 54.3 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 96.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=O)[CH2:6][CH2:5]2.N1C2C=CC=CC=2C=NC=C1>>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:18]2[C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH2:5][CH2:6][N:7]([C:8]=34)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Cl)ccc32)CC1
Agent: C1=CNc2ccccc2C=N1
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1

Procedure:
It is predicted that if the N-[2-(5-chloro-2,3-dihydro-1H-indol- 1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 12a is treated in the manner of Example 4c that 6-(4-methyl-1-piperazinyl)-4-chloro-1,2-dihydrobenzo[b]3,2,1-jk][1,4]benzodiazepine will be obtained.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[C:3]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([C:13]3[S:14][CH:15]=[C:16]([C:18]([O:20]C)=[O:19])[N:17]=3)=[C:8]([F:22])[CH:7]=2)[CH2:2]1.[Li+].[OH-].Cl>CO.C1COCC1.O.CCOC(C)=O>[F:12][C:10]1[CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:7]=[C:8]([F:22])[C:9]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[N:17]=1
Reactant: COC(=O)c1csc(-c2c(F)cc(C3=CCOC3)cc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1csc(-c2c(F)cc(C3CCOC3)cc2F)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
This mixture was diluted with 30 mL MeOH and ran through an H-cube hydrogenator (1 mL/min, 60 bar, 70 deg C.) to provide, after concentration, methyl 2-(2,6-difluoro-4-(tetrahydrofuran-3-yl)phenyl)thiazole-4-carboxylate (44 mg). This ester was diluted with THF (3 mL) and water (1.5 mL) and LiOH (6.5 mg, 2.0 equiv.) was added. After stirring for 2.5 hours at rt, the mixture was neutralized with 1 N HCl(aq), diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (42 mg, quant).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[CH:33]12[CH2:39][CH:36]([NH:37][CH2:38]1)[CH2:35][N:34]2C(OC(C)(C)C)=O>>[CH:33]12[CH2:39][CH:36]([NH:37][CH2:38]1)[CH2:35][N:34]2[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CC3CC2CN3)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Alfa Aesar, Cat. No. L20131). LCMS (M+H)+: m/z=417.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: C1COCCN1
Product: O=C1OCc2nc(CCCN3CCOCC3)ccc21

Procedure:
In a process similar to that described in Preparation 8, 3-(5-oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde and morpholine are reacted to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([SH:14])[N:3]=1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[S:20][CH:21]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[S:20][CH:21]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CSc1c(C#N)c(N)nc(S)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
250 mg (1.13 mmol) of 2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile, 412 mg (1.69 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 378 mg (4.50 mmol) of sodium bicarbonate are combined in 5 ml of DMF and stirred at room temperature for 12 h. A voluminous solid precipitates out, which solid is filtered off using a glass frit, washed three times with water and twice with diethyl ether and dried. This gives a white powder.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(O)(=O)C.C(OCC)(=O)C>[C:2](=[O:1])([O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22])[NH2:3]
Reactant: N#C[O-]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C/C(=C\COC(N)=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
6.6 g of sodium cyanate was added to a solution of 10.0 g of phytol dissolved in 50 ml of acetic acid, in small portions. The resulting mixture was stirred for 6 hours at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of ethyl acetate. The solution was washed with 3% aqueous sodium hydrogen-carbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 10.0 g (yield: 87%) of oily phytyl carbamate.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]([NH:28][NH2:29])=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>C(O)(=O)C>[Cl:17][C:18]1[C:19]([N:28]=[N:29][C:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[OH:16])=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2ncc(C(F)(F)F)cc2Cl)c2ccccc2c2ccccc12
Temperature: 100 °C

Procedure:
Next, a reaction flask was loaded with acetic acid (15 ml) and 9,10-phenanthrenequinone (5.0 g), and the temperature was raised to 100° C. with stirring to dissolve 9,10-phenanthrenequinone. To the resultant, the crystals of 3-chloro-2-hydrazino-5-(trifluoromethyl)-pyridine (5.0 g) was added in 30 minutes. After stirring at 100 to 105° C. for one hour, the reaction mixture was filtrated. After being washed with methanol, the obtained crystals were dried to give intended crystals (5.6 g).
Reaction SMILES: Br[CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:27]C(=O)C(Cl)(Cl)Cl>[Zn].C(O)(=O)C>[CH3:8][C@@H:7]1[C@:3]2([O:35][CH2:36][C@H:37]([CH3:39])[CH2:38][CH2:2]2)[O:4][C@H:5]2[CH2:23][C@@H:22]3[C@@:9]([CH3:34])([C@@H:6]12)[C@@H:10]([OH:27])[C@H:11]([OH:26])[C@H:12]1[C@H:21]3[CH2:20][CH2:19][C@@H:18]2[C@:13]1([CH3:25])[CH2:14][CH2:15][C@H:16]([OH:24])[CH2:17]2
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)[C@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)-spirostan-3,11-diol was reduced with zinc and acetic acid to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Reactant: CC(C)C(=O)Cl
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1Cl
Reaction time: 18 h
Yield: 40 %

Procedure:
Isobutyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 18 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (75 mg, 40%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](OS(C)(=O)=O)[CH:8]=[CH2:9].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[CH:32]5)[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>CN(C=O)C.C(Cl)Cl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]3[CH:30]([CH3:31])[C:29]45[CH2:38][CH:26]([O:27][C:28]4=[CH:35][C:34](=[O:36])[C:33]([OH:37])=[C:32]5[CH2:9][CH:8]=[CH2:7])[CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CC1C(c2ccc3c(c2)OCO3)CC2CC13C=C(O)C(=O)C=C3O2
Reactant: C=CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC1=C(O)C(=O)C=C2OC3CC(c4ccc5c(c4)OCO5)C(C)C21C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (172.7 mg, 1.25 mmol) and mesyl allyl ether (113 mg, 0.83 mmol) are added to a stirred solution of 4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one (109, as prepared in Example 54) in DMF (4 ml). The reaction is stirred at room temperature overnight, after which time TLC still shows unreacted starting material present. An additional 50 μl mesyl allyl ether is then added to the reaction and the reaction is then starred for another 24 hours. The reaction is diluted with methylene chloride and washed with 10% HCl followed by water. The extract is dried over sodium sulfate and concentrated in vacuo. The reaction is best purified by medium pressure liquid chromatography (MPLC) (i.e., flash chromatography on silica gel (25 g, 1:1 hexane-ethyl acetate as eluant) produces a contaminated product as determined by 1H NMR and flash chromatography on silica gel (30 g silica, 1:1:1 hexane-ethyl ether-methylene chloride) also produces a contaminated product as determined by 1H NMR). M+(CI)=367. 1H NMR: 0.64 (3H, d), 1.67 (1H, dd), 1.89 (1H, d), 2.06 (1H, m), 2.26 (2H, m), 2.49 (3H, m), 2.72 (1H, dd), 3.05 (1H, t), 5.08 (3H, m), 5.92 (2H, s), 6.15 (1H, s), 6.65 (3H, m).
Reaction SMILES: ClC1C=CC(OC2C=CC(CCO[C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=CC=2)=CC=1C(F)(F)F.[CH3:36]CN(C(C)C)C(C)C.CI>ClCCl>[CH3:36][N:19]1[CH:20]=[C:21]([CH2:25][C:26]2[CH:31]=[N:30][CH:29]=[N:28][CH:27]=2)[C:22](=[O:24])[N:23]=[CH:18]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: ClCCl
Product: Cn1cnc(=O)c(Cc2cncnc2)c1
Yield: 43.8 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (45 mg, 0.089 mmol) in dichloromethane (DCM) (2 mL) was added DIPEA (0.031 mL, 0.179 mmol) and MeI (8.39 μL, 0.134 mmol). The mixture was purified by reverse phase biotage affording 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy})phenyl)ethyl]oxy}-1-methyl-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (20 mg, 0.039 mmol, 43.2% yield) LCMS: rt=3.37 min, [M+H+]=517
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([C@@H:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:31][CH:32]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC[C@@H](CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (900 mg, 2.9 mmol) was reacted with (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (900 mg, 2.7 mmol) to afford the desired product (190 mg, 15%) as a yellow solid: ESI MS m % z 493 [C28H32N2O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.COC(=O)CCC1C=C(SC#N)C(C)=CC=1O>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(=O)oc2c1
Agent: COC(=O)CCc1cc(SC#N)c(C)cc1O
Product: Cc1ccc2c(c1)OC(=O)CC2

Procedure:
Compound 15A was prepared according to the method of example 1A utilizing compound 7-methyl-chromen-2-one. MS: 163 (M+1)+. Preparation of 3-(2-Hydroxy-4-methyl-5-thiocyanato-phenyl)-propionic acid methyl ester (Compound 15B)
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:21])([CH3:20])[CH:17]([OH:19])[CH3:18])=[CH:11][CH:10]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH3:21][C:16]([CH3:20])([O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7](=[O:22])[C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:10][CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 2-ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.2 g) in dichloromethane (6 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.21 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1>CCO.[Rh]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2occc2c1
Agent: [Rh]
Solvent: CCO
Product: Clc1ccc2c(c1)CCO2
Yield: 90.8 %

Procedure:
5-Chloro-benzofurane (2 g, 13.11 mmol) in dry EtOH (20 ml) was hydrogenated over 10% Rh/C (251 mg) catalyst at room temperature under atmospheric pressure. When H2 absorption ceased the catalyst was filtered off and the filtrate was concentrated in vacuo to give 1.84 g (91%) of (33) as a colourless solid. 1H-NMR (80 MHz, CDCl3) δ 7.00 (d, 2H, J=8.53 Hz), 6.62 (d, 1H, J=8.53), 4.5 (t, 2H), 3.11 (t, 2H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]1[C:18]([O:25][CH3:26])=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:24][C:23]1[CH:22]=[C:21]2[C:19](=[C:18]([O:25][CH3:26])[C:17]=1[F:16])[N:20]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1c(N)ccc(F)c1F
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
2.84 g (0.013 mole) of diethyl ethoxymethylenemalonate were added to 1.74 g (0.011 mole) of 3,4-difluoro-2-methoxyaniline (VIII) (prepared as described in Preparation 13). The mixture was then stirred at 140°-150° C. for 3 hours, after which 20 ml of diphenyl ether were added, and the mixture was stirred at 240°-250° C. for 1 hour. At the end of this time, the mixture was allowed to cool to room temperature, and then hexane was added to precipitate crystals, which were collected by filtration. 1.60 g of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) were obtained as colorless crystals.