Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]COC)[C:6]([OH:23])=[C:5]([O:24][CH3:25])[CH:4]=1.Cl.[NH4+].[OH-]>CO>[CH3:26][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:6]([OH:23])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COCOCCCCCCCCCCc1nc(N(C)C)cc(OC)c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N(C)C)nc(CCCCCCCCCCO)c1O

Procedure:
To a stirred solution containing 6-(Dimethylamino)-4-methoxy-2-(10-(methoxymethoxy)decyl)pyridin-3-ol in 5 mL of methanol was added a drop of conc HCl. The reaction mixture was stirred at reflux for 2 h. A drop of conc NH4OH was added and the mixture was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (1×10 cm). Elution with 9:1 dichloromethane-methanol afforded the expected product as a yellowish oil: yield 7 mg (40%); silica gel TLC Rf 0.2 (9:1 dichloromethane-methanol); 1H NMR (methanol) δ 1.29 (br m, 12H), 1.49 (quint, 2H, J=6.8 Hz), 1.62 (quint, 2H, J=7.2 Hz), 2.66 (dd, 2H, J=7.6, 7.6 Hz), 3.00 (s, 6H), 3.49 (t, 2H, J=6.8 Hz), 3.90 (s, 3H) and 6.11 (s, 1H); 13C NMR (methanol) δ 25.50, 28.06, 29.08, 29.13, 29.14, 29.20, 29.28, 30.09, 32.22, 38.16, 38.16, 54.90, 61.57, 87.88, 132.75, 143.86, 154.04 and 157.27; mass spectrum (APCI), m/z (M+H)+325.2489 (C18H33N2O3 requires 325.2491).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[ClH:28].[NH2:29][C@H:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]>>[ClH:28].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:29][C@H:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]
Reactant: C[C@@H](N)CC(=O)O
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: C[C@H](CC(=O)O)NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (0.040 g, 0.11 mmol) and (R)-3-aminobutanoic acid hydrochloride (0.056 g, 0.40 mmol) according to Reference R and general procedure for reductive amination afforded (R)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)butanoic acid hydrochloride. MS (ESI) m/z: calculated: 461.2; Observed: 462.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCCc3ccc(CC)cn3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (519 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (228 mg, yield: 47%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 89–90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]2[CH:6]([CH:7]3[O:12][CH:10]2[CH2:9][CH2:8]3)[C:5](=[O:13])[CH:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[I:20]I>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[I:20][C:4]1[C:5](=[O:13])[CH:6]2[CH:11]([C:3]=1[O:2][CH3:1])[CH:10]1[O:12][CH:7]2[CH2:8][CH2:9]1
Reactant: II
Reactant: COC1=CC(=O)C2C3CCC(O3)C12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Product: COC1=C(I)C(=O)C2C3CCC(O3)C12
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A flask is charged with 5-methoxy-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (3.96 g, 22 mmol), cerium ammonium nitrate (13.3 g, 24.2 mmol) and iodine (6.73 mg, 26.5 mmol) and then purged with nitrogen. Anhydrous acetonitrile (120 ml) is added, and the reaction heated to 40° C., with stirring for 2 hours. The crude reaction mixture is poured onto a saturated aqueous solution of sodium metabisulphite (250 ml) and extracted with dichloromethane (2×250 ml). The combined organics are dried over magnesium sulphate, filtered, and the solvent is removed under reduced pressure to give 4-Iodo-5-methoxy-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (5.70 g)
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:12].[ClH:14].[NH:15]([C:22]1[S:23][CH2:24][C:25](=[NH:27])[N:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:14].[NH:12]=[C:6]1[C:7]2[C:3](=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][CH:8]=2)[C:4](=[C:24]2[S:23][C:22]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: Cc1ccc2c(c1C)C(=N)NC2=N
Reactant: N=C1CSC(Nc2ccccc2)=N1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: Cc1ccc2c(c1C)C(=C1SC(Nc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 4,5-dimethyl-1,3-diiminoisoindoline and 2-anilino-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-4,5-dimethyl-3-(2-anilino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:45]1[CH2:46][CH2:47][CH:42]([C:40]([C:32]2[N:31]([CH2:30][C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)=[O:41])[CH2:43][CH2:44]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Reactant: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccco2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: O
Product: CC(=O)Nc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.07 g, 0.16 mmol) DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.08 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.4 Hz, 1 H), 7.74 (t, J=8.2 Hz, 1 H), 7.68 (d, J=8.2 Hz, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.56 (t, J=8.5 Hz, 1 H), 7.48 (d, J=7.4 Hz, 2 H), 7.22 (d, J=7.5 Hz, 2 H), 7.08 (d, J=8.9 Hz, 2H), 5.42 (s, 2 H), 2.22 (s, 3 H), 1.58 (s, 6 H). MS: [M+Na]: m/z=501.3, [M+H]: m/z=479.3. HPLC: 95.9% (RT-2.32 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33])([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:24]([C:21]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:8]([CH3:9])[CH2:7][N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[C:23]=2[CH:22]=1)=[O:25])([O-:29])=[O:28]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3ccccc3[N+](=O)[O-])cc21
Yield: 36.9 %

Procedure:
By working in a manner similar to that described in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (2.5 g) in dichloromethane (50 cc) and with 2-nitrobenzylamine (2.1 g), N-(2-nitrobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.1 g) is obtained, after recrystallization in isopropyl ether, in the form of yellow crystals, m.p. 95° C.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([NH:16][C@H:17]([C:28]1[S:29][CH:30]=[C:31]([CH2:33][CH3:34])[N:32]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:15])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:41](=[N:44]O)([NH2:43])[CH3:42]>C1(C)C=CC=CC=1>[CH2:33]([C:31]1[N:32]=[C:28]([C@@H:17]([NH:16][C:14](=[O:15])[CH:8]([C:9]2[O:11][N:44]=[C:41]([CH3:42])[N:43]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[S:29][CH:30]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(CC)cs1
Reactant: CC(N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)C(Cc2ccccc2)c2nc(C)no2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Ethyl 2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-oxopropanoate is dissolved in toluene (5 mL) and heated to reflux. Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added. and treated with 80 mg potassium carbonate and 43 mg acetamide oxime at reflux. The reaction mixture is cooled to room temperature, filtered and concentrated. The residue is chromatographed over silica to afford 0.221 g (94%) of the desired product as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccc(N2CCSCC2)cc1

Procedure:
A solution of 23.47 g of 4-(p-nitrophenyl)-tetrahydro-4H-1,4-thiazine in 1.5 l of dioxane is hydrogenated over Raney-nickel until the hydrogen uptake has finished. Thereafter, the catalyst is removed by filtration, washed well with dioxane and the filtrate is evaporated in vacuo. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-aminophenyl)-tetrahydro-4H-1,4-thiazine of melting point 109°-111°.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>C(O)C>[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Yield: 89.7 %

Procedure:
23.2 g of cyclopropylamine are added dropwise to a solution of 123.9 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (5) in 250 ml of ethanol, while cooling with ice and stirring. When the exothermic reaction has abated, stirring is continued for a further hour at room temperature, the solvent is stripped off in vacuo and the residue is recrystallised from cyclohexane petroleum ether. 115 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylamino-acrylate (6) of melting point 63°-65° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25]>>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:15]([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[CH:16][CH2:17]1
Reactant: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanone (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure in Example 1, step (f). Mass spectrum (APCI, m/z): Calcd. for C31H42N4O3Si, 547.3 (M+H). found 547.0.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:10][C:11](=[O:40])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3Br)[CH:22]=2)=[CH:16][C:15]=1[CH3:39]>>[CH3:39][C:15]1[CH:16]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:29]=3[O:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[CH3:8])[CH:22]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][C:11]([OH:40])=[O:10]
Reactant: Cc1ccccc1O
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3C)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 38 by using o-cresol and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 229 mg (21%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [S:1]1[C:5]([NH:6][CH2:7][CH2:8][CH3:9])=[N:4][N:3]2[CH:10]=[CH:11][N:12]=[C:2]12.[I:13]N1C(=O)CCC1=O>C(#N)C>[I:13][C:10]1[N:3]2[C:2]([S:1][C:5]([NH:6][CH2:7][CH2:8][CH3:9])=[N:4]2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCNc1nn2ccnc2s1
Solvent: CC#N
Product: CCCNc1nn2c(I)cnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.6 %

Procedure:
663 mg of imidazo[2,1-b][1,3,4]thiadiazol-2-yl-propyl-amine were dissolved in 20 ml of acetonitrile. 822 mg of N-iodosuccinimide were added to the solution. The reaction mixture was stirred for 4 h at room temperature. For work-up, the mixture was cooled on ice and filtrated. 410 mg of the desired product were obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=[O:17])/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15]C)=[O:13]>C(O)CC>[O:17]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: Nc1ccccc1N
Solvent: CCCO
Product: COC(=O)CC1Nc2ccccc2NC1=O

Procedure:
Orthophenylenediamine (10 g, 92.4 mmol) and diethyl maleate (45 g, 646.8 mmol) were refluxed for 75 h in propanol. The solvent was removed using a rotary evaporator and the residue was purified by column chromatography (ethyl acetate/hexane 1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1>>[F:24][C:13]([F:12])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[N:15]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(=O)Cc1ccc(Br)cc1
Product: CC(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-bromophenylacetone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19]CC3C=CC(OC)=CC=3)=[N:15][CH:16]=2)[N:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35]>FC(F)(F)C(O)=O>[NH2:19][C:14]1[N:13]=[C:12]2[N:11]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: COc1ccc(CNc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Yield: 2.7 %

Procedure:
A solution of 40 mg (0.96 mmol) of 3-(2,6-dichlorophenyl)-7-(4-methoxybenzyl)amino-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of trifluoroacetic acid was heated at reflux for 5 hours. The mixture was evaporated and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of 2M aqueous sodium hydroxide. The organic phase was dried over magnesium sulfate, filtered and evaporated and the residue was subjected to column chromatography on silica gel using dichloromethane/methanol (20:1) for the elution. Product-containing fractions were combined and evaporated to give 10 mg (27%) of 7-amino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point >300° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:34]=1[C:40](=[O:42])[CH3:41].[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53](O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:39][C:37]2[CH:36]=[CH:35][C:34]([C:40](=[O:42])[CH3:41])=[C:33]([F:32])[CH:38]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C

Procedure:
In a 500 mL round bottom flask, diethyl azodicarboxylate (16.9 g, 97.3 mmol) and triphenylphosphine (25.5 g, 97.3 mmol) in tetrahydrofuran (200 mL) were cooled to 0° C. 1-(2-Fluoro-4-hydroxy-phenyl)-ethanone (10.0 g, 64.9 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (15.67 g, 77.9 mmol) in tetrahydrofuran (100 mL) were added. The reaction was warmed to ambient temperature 14 h. The solvents were concentrated under vacuum and methylene chloride (100 mL) and hexanes (500 mL) were added. The solids were filtered off. The mother liquor was concentrated under vacuum and chromatographed through silica gel with hexanes/ethyl acetate (7:3) as eluent to produce 17.5 g (80%). Mp 72-73° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)Cl.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:22][C:18]1[N:17]=[C:16]([N:2]([CH3:1])[S:3]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH:21]=[CH:20][CH:19]=1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Clc1cccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2cccc(Cl)n2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
N-Methyl-p-toluenesulfonamide (0.2 g, 1 mmol) was added to a microwave vial equipped with a stir bar. DMF (3 mL) was added to the mixture, followed by NaH (0.13 g, 5.40 mmol), and the reaction solution was allowed to stir for 20 minutes. Then 2,6-dichloropyridine (0.24 g, 1.6 mmol), palladium(II) acetate (0.0242 g, 0.108 mmol) and Xantphos (0.024 g) were added to the mixture. The vial was capped and placed in the CEM microwave and heated for 10 minutes at 100° C. The mixture was diluted with DCM and saturated NaHCO3. The aqueous layer was extracted with 4:1 DCM/MeOH three times, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (1-10% EtOAc/hexanes) to give N-(6-chloropyridin-2-yl)-N,4-dimethylbenzenesulfonamide (0.1 g, 31.2% yield) as a colorless oil. MS (ESI pos. ion) m/z: 297 (MH+). Calculated exact mass for C13H13ClN2O2S: 296.
Reaction SMILES: CCCCC.[C:6](Cl)([Cl:8])=[O:7].[C:10]([O:14][O:15][C:16](=[O:20])[CH2:17][CH2:18][OH:19])([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1>C(OCC)C>[Cl:8][C:6]([O:19][CH2:18][CH2:17][C:16]([O:15][O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:20])=[O:7]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OOC(=O)CCO
Solvent: CCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OOC(=O)CCOC(=O)Cl

Procedure:
To 75 ml. of pentane at -10° to +5° C was added 39.6g. of phosgene. To this mixture was added a mixture of t-butyl-3-hydroxyperoxypropionate (38g. 0.2 moles of 85% pure products) and pyridine (15.8g. 0.2 moles) in diethyl ether over a period of one hour.