Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.NC(N)=[S:12].CC(CC)=O>O>[SH:12][C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)nn1
Reactant: NC(N)=S
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc(S)nn1
Yield: 23.4 %

Procedure:
A mixture of 3-chloro-6-methoxy pyridazine (0.69 mol, 100 g), thiourea (1.38 mol, 105 g) and ethyl methyl ketone (1.8 L) was refluxed for 3 hours. The reaction was cooled and the supernatant was poured into water and extracted with 1M sodium hydroxide (4×100 mL). The sodium hydroxide solution was washed with EtOAc (2×50 mL), the aqueous extract was acidified with sufficient conc. HCl to lower the pH to 5 and the resulting yellow solid was collected and air-dried to obtain 3-mercapto-6-methoxy pyridazine (24%, 23 g); mp 198° C.-200° C.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:52]([F:56])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: FC1(F)CNC1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoroazetidine hydrochloride and isolated as light-yellow gum (11.9 mg, 64%). MS(m/e): 393.4 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](C2C(=O)CC(C(F)(F)F)CC=2O)[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[F:36][C:37]([F:53])([F:52])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]2[CH2:49][C:48](=[O:50])[CH2:47][C:46](=[O:51])[CH2:45]2)=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[C:46](=[O:51])[CH2:45][CH:44]([C:41]3[CH:40]=[CH:39][C:38]([C:37]([F:52])([F:53])[F:36])=[CH:43][CH:42]=3)[CH2:49][C:48]=2[OH:50])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CC(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3ccc(C(F)(F)F)cc3)CC2=O)cc1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12), using 5-(4-(trifluoromethyl)phenyl)cyclohexane-1,3-dione (500 mg, 1.95 mmol) as starting material. Yield: 930 mg; ESI mass spectrum [M+H]+=574, Retention time HPLC: 0.85 min (V011_S01).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:17]=1
Reactant: O=c1[nH]c(-c2ccccc2F)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 0 °C
Yield: 73 %

Procedure:
2-(2-Fluoro-phenyl)-3H-quinazolin-4-one from Step B (0.86 g, 3.5 mmol) was suspended in chloroform in a 50 ml round bottomed flask equipped with magnetic stirrer. The flask was cooled to 0° C. and to it was added thionyl chloride (1.2 ml) drop wise followed by N,N-dimethylformamide (0.01 ml) and the mixture heated to 80° C. for 4 hrs. The solvent was removed by evaporation in a rotary evaporator to leave a title compound as a solid (0.68 g, 73%). MS (ES) 259.1 (M+H)+
Reaction SMILES: C[C:2]1[CH:9]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([Br:25])=[CH:20][C:19]=3[CH3:26])[C:14]([N+:27]([O-:29])=[O:28])=[C:13]([CH3:30])[N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[CH:36](N(C)C)[N:37]([CH3:39])[CH3:38])(C)(C)C>CN(C=O)C>[Br:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([NH:17][C:15]2[C:14]([N+:27]([O-:29])=[O:28])=[C:13](/[CH:30]=[CH:36]/[N:37]([CH3:39])[CH3:38])[N:12]=[C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[CH:2][CH:9]=3)[N:16]=2)=[C:19]([CH3:26])[CH:20]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Nc2nc(C)c([N+](=O)[O-])c(Nc3c(C)cc(Br)cc3C)n2)ccc1C#N
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Nc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A dried flask under argon was charged with methyl 4-(4-(4-bromo-2,6-dimethylphenylamino)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (4.3 g, 9.5 mmol) dissolved in anhydrous DMF (95 ml) followed by tert-butoxybis(dimethylamino)methane (2.4 ml, 11.4 mmol). The reaction mixture was heated to 60° C. and stirred overnight under argon. Upon completion the reaction was cooled to ambient temperature, concentrated to half volume, and quenched with H2O (100 ml). The aqueous solution was extracted with ethyl acetate (3×70 ml) and the collected organic fractions were washed with brine (100 ml), dried with MgSO4, filtered and concentrated. Silica gel chromatography (ethyl acetate:Hexanes=50:50) yielded (E)-4-(4-(4-bromo-2,6-dimethylphenylamino)-6-(2-(dimethylamino)vinyl)-5-nitropyrimidin-2-ylamino)benzonitrile (3.21 g, 67%) as a brown solid. m/z=508 [M+1].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:18]1(/[CH:21]=[CH:22]/[C:23](Cl)=[O:24])[CH2:20][CH2:19]1.[NH4+].[Cl-]>C1COCC1>[CH:18]1(/[CH:21]=[CH:22]/[C:23]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])=[O:24])[CH2:20][CH2:19]1
Reactant: O=C(Cl)/C=C/C1CC1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(/C=C/C1CC1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C

Procedure:
(R)-(-)-4-Phenyl-2-oxazolidinone (39.12 g, 0.240 mmol, Aldrich) was dissolved in THF (600 mL), and the solution was cooled to -78° C. and flushed with N2. n-Butyllithium (2.5M in THF, 96.0 mL, 0.240 mmol) was introduced over 25 minutes. The compound from step 1b (0.276 mmol) was added while maintaining the temperature at -78° C., and the mixture was stirred at this temperature for half an hour. The mixture was stirred as it was allowed to warm to room temperature. Saturated aqueous NH4Cl solution was added, the mixture was stirred for 10 minutes and the THF was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water, 5% aqueous NaHCO3 and brine, then dried over Na2SO4. The solvent was removed to afford the title compound, which was recrystallized from ethyl acetate:hexane to give the title product (54.660 g, 89% yield). MS m/z 258 (M+H)+, 275 (M+NH4)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[C:30]1(=[CH:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]1.N12CCCN=C1CCCCC2>C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C:30]5([CH2:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]5)[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: N#CC=C1CCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2(CC#N)CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a solution of 1-[(1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (10 mg, 0.022 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (0.1 mL) was added cyclobutylideneacetonitrile (4.1 mg, 0.044 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (13 μL, 0.087 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetonitrile and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (4.3 mg, 41%). The product was isolated as a single enantiomer. LCMS calculated for C25H31ClN7O (M+H)+: m/z=480.2; Found: 480.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][O:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[O:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCc2occc2C(O)C1
Product: CN1CCc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepin-4-ol (Reference Example 27) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18]O)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:20])/[CH2:18][N:44]2[C:40](=[O:50])[C:41]3[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:43]2=[O:45])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (E)-3-(3,5-difluoro-4-phenoxyphenyl)-2-methylprop-2-en-1-ol (Intermediate 93.1) (410 mg, 1.49 mmol) in dry toluene (7.45 mL) under N2 was added PPh3 and phthalimide. The resulting solution was cooled to 0° C. and diethyl azodicarboxylate (DEAD, 0.748 mL) was added dropwise over several minutes. The reaction was allowed to warm to room temperature and stirred overnight. After diluting with EtOAc (20 mL), the organic layer was washed with water (2×30 mL), brine (30 mL) and dried over Na2SO4. After removal of solvent, the resulting residue was applied to a silica gel column (15% EtOAc in hexanes) to yield 385 mg of the title compound (63%) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH2:21][CH:20]3[CH2:22][CH:17]2[CH2:18][N:19]3C(=O)C)=[CH:13][CH:12]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:19]1[CH2:18][C@@H:17]2[CH2:22][C@H:20]1[CH2:21][N:16]2[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:27][CH:26]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.2 %

Procedure:
To a solution of 1-[5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone (0.2 g, 0.49 mmol) in CH2Cl2 (5 mL) was added Et3N (0.41 mL, 3.0 mmol) and methanesulfonyl chloride (57 μL, 0.74 mmol) and the resulting solution was stirred at rt for 14 h. The reaction mixture was concentrated and the crude residue was partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was separated, dried (Mg2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 15% CH3OH in CH2Cl2) afforded the title compound as clear oil (0.13 g, 62%). MS (ESI): mass calcd. for C21H23N3O2S2, 413.56; m/z found, 414.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=7.8 Hz, 1H), 7.81 (dd, J=7.8, 0.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (d, J=2.0 Hz, 2H), 4.31 (br s, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.75 (d, J=13.8 Hz, 1H), 3.62-3.60 (m, 1H), 3.57 (br s, 1H), 3.24 (dd, J=9.3, 2.3 Hz, 1H), 2.90-2.89 (br m, 4H), 2.85-2.83 (br m, 1H), 1.96-1.94 (m, 1H), 1.74-1.72 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[O:47][CH3:48]>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Reactant: COc1ccccc1I
Product: COc1ccccc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Yield: 77 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (140 mg, 0.211 mmol) and 1-iodo-2-methoxybenzene following General Procedure A. Flash chromatography (2% EtOAc/hexanes) yielded the title compound as a white solid (78 mg, 77%): 1H NMR (CDCl3, 400 MHz) δ 7.81 (dd, 1H, J=9.2, 6.0 Hz), 7.49 (s, 1H), 7.30-7.27 (m, 3H), 7.19-7.16 (m, 3H), 7.07-7.05 (m, 1H), 6.99 (d, 1H, J=8.4 Hz), 4.85 (t, 1H, J=6.8 Hz), 3.98 (s, 3H), 2.58 (t, 2H, J=8.0 Hz), 1.95-1.91 (m, 2H), 1.63-1.60 (m, 2H), 1.38-1.34 (m, 6H), 0.91 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 160.7, 152.7, 148.0, 134.0, 133.5, 133.3, 131.0, 130.9, 130.7, 125.9, 122.4, 115.9, 73.8, 60.5, 41.6, 41.1, 36.6, 34.3, 34.3, 30.9, 30.3, 23.3, 0.2, 0.0.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)[CH:24]=[CH:25][N:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCCCCNc1cc(C#N)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 18.1 %

Procedure:
Methyl thiosalicylate (0.44 g, 2.6 mmol) and 2-(hexylamino)isonicotinonitrile (0.26 g, 1.3 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.40 ml, 2.9 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs, subjected to a silica gel (50 g) chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.08 g, 18%) as white crystals.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:3]([CH:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[O:5])[CH2:12][CH2:11]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C2CCCN2)CC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-tert-butoxycarbonyl)-L-proline was reacted with 1-methylpiperazine to give (2S)-1-tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.05 (m, 4H), 2.1–2.25 (m, 1H), 2.32 (s, 3H), 2.35–2.5 (m, 4H), 2.6–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum: M+H+ 242.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc2ccccc12
Yield: 82.9 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.0 g, 25 mmole), naphthaleneboronic acid (4.0 g, 23 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (5.4 g, 83%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.O[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([O:26][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccccn1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Oc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a stirred suspension of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (prepared according to the procedure described in WO 2007/079162, 1.50 g, 3.30 mmol) in dichloromethane (15 mL) at room temperature was added oxalyl chloride (0.58 mL, 6.60 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (10 mL) and added to a stirred suspension of 2-hydroxypyridine (0.38 g, 3.96 mmol) and K2CO3 (1.37 g, 9.90 mmol) in dichloromethane (15 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a short pad of Celite® diatomaceous filter aid, and the pad was rinsed with dichloromethane. The combined filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title product as a yellow solid (0.80 g, 46% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][CH:37]([NH2:39])[CH3:38])[CH:35]=1>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:39][CH:37]([CH3:38])[CH2:36][C:34]4[CH:35]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=4[CH3:40])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1ccc(F)cc1CC(C)N
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 55 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.48 g, 1.20 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.24 g, 1.44 mmol), Hunig,s base (0.78 g, 6.00 mmol), and 10 mL of anhydrous 1-butanol was heated at reflux for 12-13 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.35 g of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.24 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.99 (s, 1H, ArH), 7.32 (t, J=6.5 Hz, 1H, ArH), 7.15-7.08 (m, 2H, ArH), 6.91-6.87 (m, 1H, ArH), 6.16 (d, J=7.5 Hz, 1H, ArH), 4.22-4.18 (m, 1H, CH), 3.73-3.71 (m, 2H, CH2), 2.97-2.96 (m, 2H, CH2), 2.86 (s, 3H, CH3), 2.72-2.68 (m, 2H, CH2), 2.36 (s, 6H, 2×CH3), 2.27 (s, 3H, CH3), 1.34 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, negative) m/z 529.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 7.4 g. (24.5 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine and 2.0 g. of 10% palladium-on-carbon in 150 ml. of ethanol and 75 ml. of ethyl acetate is stirred under one atmosphere of hydrogen for 2.5 hours. The reaction is filtered through diatomaceous earth and evaporated. Crystallization of the residue from ether-pentane gave 4.6 g. (62%) of the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=[C:12]([Cl:23])[N:11]=1)(=O)=O.ClC1N=C(N2CCOC[C@H]2C)C=C(CCl)N=1.[I-].[Na+]>CC#N.CCOC(C)=O>[Cl:23][C:12]1[N:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[CH:15]=[C:10]([CH2:9][S:2][CH3:1])[N:11]=1
Reactant: C[S-]
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: C[C@@H]1COCCN1c1cc(CCl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Reaction time: 16 h
Yield: 91 %

Procedure:
In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20° C. to 18° C. over the addition and then in the next 5 minutes rose to 30° C.). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.07 (3H, s), 3.11-3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92-4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.