Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=0.89 min; [M+H]+=366.19.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:16].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.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:7][C:6]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=2)=[N:3][S:4][C:5]=1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[CH3:14])=[O:10]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
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: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
Degas a solution of (R,R)—N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.500 g, 1.471 mmol), (4-ethoxyphenyl)boronic acid (0.485 g, 2.941 mmol), DMF (3 mL) and toluene (29 mL) with nitrogen. Add sodium carbonate (2 M) (4.41 mmol) and Pd(PPh3)4 (0.255 g, 0.221 mmol); then seal under nitrogen. Heat at 60° C. overnight. Add 100 mg of Pd(PPh3)4 and heat for 1 more day. Dilute with EtOAc and wash with brine. Separate and evaporate. Chromatography on silica gel, eluting with 15-50% EtOAc in hexane, followed by crystallization from EtOAc and hexane affords (R,R)—N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 53.5% ES-MS: 380.0 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[Cl:1])=[N:6][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N=C(N)c1ccc(F)cc1Cl
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc(F)cc2Cl)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=396.8 (M+), was prepared from 2-chlor-4-fluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]1(/[CH:13]=[CH:14]/[C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:13][CH2:14][C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: N#C/C=C/c1cn2c3c(cccc13)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#CCCc1cn2c3c(cccc13)CCC2

Procedure:
(E)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acrylonitrile (348 mg, 1.7 mmol) and 10% Pd—C (50 mg) in methanol (20 ml) were stirred at room temperature under 1 atmosphere of hydrogen gas for 6 hours. The mixture was filtered through celite washed with methanol and evaporated to dryness to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionitrile as an off white solid (310 mg). 400 MHz 1H NMR (CDCl3) δ: 7.32 (d, J=8.4 Hz, 1H), 7.03-6.96 (m, 2H), 6.91 (d, J=6.8 Hz, 1H), 4.11 (t, J=5.6 Hz, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.26-2.19 (m, 2H); LCMS: 211 [M+H].
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:45][CH3:46].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH2:45][CH3:46])[CH:33]=[CH:32][C:31]=4[F:37])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCI
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(O)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OCC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-hydroxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (50 mg) in DMF (989 μL) were added cesium carbonate (97 mg) and iodoethane (12.0 μL) at 0° C., and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (49.8 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13]C(C)(C)C(C)(C)[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][N:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1)[CH3:2].F.[K]>CO>[CH2:1]([C:3]1[C:4]([CH2:18][N:19]2[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]2)=[CH:5][CH:6]=[CH:7][C:8]=1[B:9]([OH:10])[OH:13])[CH3:2]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: F
Agent: [K]
Solvent: CO
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1B(O)O
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of methyl 1-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-azetidinecarboxylate (5.23 g, 14.56 mmol) in Methanol (50 mL) was added potassium hydrogen fluoride (16.17 mL, 72.8 mmol). The mixture was stirred at rt for an hour. LCMS showed that the starting material was consumed completely. The solvent was removed under the reduced pressure and the residue was acidified with HCl (1.0 M) to pH value around 3 then extracted with EtOAc (50 mL). The aqueous phase was adjusted to pH value around 6 with sat. NaHCO3 solution, the target product was collected by filtering and dried in vacuum to give (2-ethyl-3-((3-(methoxycarbonyl)azetidin-1-yl)methyl)phenyl)boronic acid (2.5 g) as a brown solid. δH (DMSO-d6, 600 MHz): 1.02 (2H, m), 2.81 (2H, m), 3.70 (4H, m), 4.23 (4H, m), 4.33 (2H, m), 7.00 (2H, m), 7.43 (1H, m), 9.93 (1H, m).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[NH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC(=O)OCc1ccccc1

Procedure:
Compound (25) (517 mg, 1.85 mmol) was treated with 4N HCl in dioxane at room temperature for 2 h. The reaction mixture was evaporated at reduced pressure, evaporated from toluene and then dried under vacuum to give crude benzyl β-alaninate hydrochloride which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([SH:26])[N:3]=1.Cl.[Cl-].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19])[CH2:14][CH2:15]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:8][C:7]2[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](c2c(C#N)c(N)nc(SCc3cccnc3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
97 mg (0.23 mmol) of the compound from Example 12A (cis isomer), 46 mg (0.28 mmol) of 3-pyridinemethyl chloride hydrochloride and 78 mg (0.93 mmol) of sodium bicarbonate are initially charged in 2 ml of dry DMF and stirred at RT for 20 h. The mixture is then filtered and the filtrate is directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.CC1C=CC(S(O[CH:43]2[CH2:46][O:45][CH2:44]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[Na+]>CCOC(C)=O.CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH:43]6[CH2:46][O:45][CH2:44]6)=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OC5COC5)ccc43)cc2s1
Temperature: 145 °C
Yield: 31 %

Procedure:
A stirred mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg, 0.23 mmol) from Step 1 of Example 171, oxetan-3-yl 4-methylbenzenesulfonate (420 mg, 1.84 mmol) from the previous step, Cs2CO3 (225 mg, 0.69 mmol), sodium iodide (276 mg, 0.69 mmol) and NMP (4 mL) was heated at 145° C. for 15 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 40:1 DCM/MeOH to afford (3aR,7aR)-2,2-dimethyl-3-(6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (35 mg, 31%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.17-7.20 (m, 2H), 6.94 (s, 1H), 6.84 (m, 1H), 5.35 (s, 2H), 5.24 (m, 1H), 5.00 (m, 2H), 4.79 (m, 2H), 3.66 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H), 2.15 (m, 1H), 1.84-1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.30-1.45 (m, 4H); LCMS (ESI) m/z 491 (M+H)+.
Reaction SMILES: CNCCNC.[CH2:7]([O:9][C:10]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=1)=[CH:16][CH:15]=2)=[O:11])[CH3:8].Br[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[N:13]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=1)=[CH:16][CH:15]=2)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)nc3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)nc3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 140 °C
Yield: 69.7 %

Procedure:
A mixture of CuI (7.14 mg, 51 mmol), N,N′-dimethyl-1,2-diaminoethane (16.7 μL, 0.153 mmol) and toluene (0.5 mL) was added to a mixture of 5-(6-isopropoxypyrid-3-yl)indole-2-carboxylic acid ethyl ester (165 mg, 0.510 mmol; see step (a)), 1-bromo-4-isopropoxybenzene (219 mg, 1.02 mmol), K3PO4 (108 mg, 0.510 mmol) and toluene (2 mL) under argon. The mixtures was heated at 110° C. for 5 h and at 140° C. for 16 h, then allowed to cool to room temperature and filtered through Celite®. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to give the sub-title compound (163 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([F:16])([F:15])[F:14].FC(F)(F)[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1N=CC=C2O.BrBr.[OH-].[Na+]>C(O)(=O)C>[C:5]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([C:11]=2[C:28]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=[CH:7][C:6]=3[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(-c3ccccc3)cnc12
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Preparation of 3-Bromo-8-(trifluoromethyl)quinolin-4-ol: 8-Trifluoromethyl-quinolin-4-ol (9.12 g, 42.8 mmol) is dissolved in acetic acid (300 mL). Bromine (2.20 mL 42.8 mmol) is dissolved in acetic acid (30 mL) and then added drop wise to the reaction over 20 min. After 0.5 h, the solution is poured into 500 mL of 2N NaOH and stirred. The white precipitate is filtered and dried in vacuo yielding the title compound as a white solid (10.3 g, 83%). mp 297-299° C.; MS (ESI) m/z 292; MS (ESI) m/z 290; HRMS: calcd for C10H5BrNF3O+H, 291.95848; found (ESI_FT, [M+H]1+), 291.95847.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18]([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18]([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CSc1ccc(-c2ccc(C(=O)CCc3ccc(OC(C)(C)C(=O)[O-])c(Cl)c3Cl)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(-c2ccc(C(=O)CCc3ccc(OC(C)(C)C(=O)O)c(Cl)c3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2,3-Dichloro-4-(3-(5-(4-(methylthio)phenyl)thien-2-yl)-3-oxopropyl)-phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-(5-(4-(methylthio)phenyl)thien-2-yl)-3-oxopropyl)phenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid. After stirring for 18 hours at room temperature, the reaction mixture is washed with water and then the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:17][CH:18]=1.[O-][Si]([O-])=O.[Mg+2]>ClCCl>[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: OCCc1cccc(F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=CCc1cccc(F)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of pyridinium chlorochromate (75.5 g, 0.35 mol) in dry dichloromethane (300 ml) under a nitrogen atmosphere was added 2-(3-fluorophenyl)ethanol (43 g, 0.31 mol) dropwise. After the addition the mixture was stirred for 1 hour, allowed to stand overnight then poured down a florisil column. The column was washed with ether and the combined filtrate and washings were evaporated to leave the crude 3-fluorophenyl acetaldehyde as an unstable liquid which was not purified further (34 g), NMR δ 9.75 (1H, t), 7.3 (1H, m), 7.05-6.9 (3H, m), 3.7 (2H, d).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([NH:15][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 68.5 %

Procedure:
2-Naphthyl sulfonyl chloride (0.17 g, 0.76 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.76 mmol) along with other reagents as mentioned in Example 1(c) to afford 0.27 g of the required product. 1H NMR (DMSO-d6): δ 5.38 (1H, brs), 6.82 (1H, d), 7.12 (1H, d), 7.22 (2H, d), 7.35 (2H, dd), 7.44 (1H, d), 7.80 (7H, m), 7.95 (2H, m), 8.15 (2H, d), 8.56 (1H, s).
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](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:39][CH3:40])[CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)[CH3:26]>>[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:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:39][CH3:40])[CH2:25][CH3:26])=[CH:38][CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Product: CCN(CC)CCOc1ccc(CNc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 238 mg (1.07 mmol) of 4-(2-diethylaminoethoxy)benzylamine was heated at 170° C. for 30 minutes. The product was purified by flash column chromatography using dichloromethane/methanol/water/acetic acid (120:14:3:2) for the elution. Product-containing fractions were combined and evaporated to give 40 mg (29%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]benzylamino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 137-138° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18](O)=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:22]([S:24](C1C=C(C2N3C(C=NC(SC)=N3)=CC=2)C=CC=1)(=[O:26])=[O:25])C.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.CC(O)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18]([S:24]([CH3:22])(=[O:26])=[O:25])=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(SC)nn23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCS(=O)(=O)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
7-(3-Ethanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol: To a mixture of Na2WO4.2H2O (62 mg, 0.19 mmol) and 7-(3-Ethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.25 g, 3.76 mmol) in methanol (40.0 mL) was added 50% H2O2 (0.65 mL, 11 mmol) and the reaction was stirred at 60° C. for 5 h. The mixture was treated with HOAc (700 uL), 50% H2O2 (0.65 mL, 11 mmol) and Na2WO4.2H2O (65 mg, 0.2 mmol) and warmed at 60° C. until reaction was completed as analyzed by LC/MS. At this time, the mixture was treated with 10% aqueous solution of Na2S2O3 (5 mL) and the resultant solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford 7-(3-ethanesulfonyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (1.33 g; Yield=97%, HPLC RT=2.51). To the above sulfone in 1,4-dioxane (4 mL) and DMSO (2.5 mL) was added an aqueous solution of 5N NaOH (11.1 mL, 55.4 mmol). The mixture was heated at 80° C., O/N, cooled in an ice bath and treated with 3M HCl until pH 4. The resulting solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford the title compound (0.675 g; Yield=88%). LC/MS: 304 (M+H); HPLC: RT=1.81 min; 1H NMR: (DMSO, δ) 11.88 (br s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 8.59 (d, J=7.7, 1H), 7.87 (d, J=7.7, 1H), 7.80 (t, 1H, J=7.7), 7.45 (d, J=4.9, 1H), 7.06 (d, J=4.9, 1H), 3.39 (q, J=7.2, 2H), 1.15 (t, J=7.2, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[C@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][O:15][C:14]2=[O:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.CO[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:11](=[O:12])[N:13]2[C@H:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][O:15][C:14]2=[O:25])[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCNC(=O)OCc1ccccc1
Reactant: O=C(CCc1ccc(F)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of (4R)-3-[3-(3,4-difluorophenyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (1 g, 2.90 mmol) in dichloromethane (29.0 ml) at −60° C. was added TiCl4 (0.335 ml, 3.04 mmol) dropwise. After 30 min, DIPEA (0.556 ml, 3.19 mmol) was added and the solution stirred at 1 h at 0° C. phenylmethyl [(methyloxy)methyl]carbamate (1.131 g, 5.79 mmol)[prepared according to Barnett, C. J. et al, Tetrahedron Lett. 1997, 38, 5, 735.] was added and the reaction mixture stirred at 0° C. for 4 h. The solution was quenched with aqueous saturated ammonium chloride solution and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-2-[(3,4-difluorophenyl)methyl]-3-oxo-3-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]propyl}carbamate (548 mg, 0.506 mmol, 17.49% yield) as a clear oil:
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[O:17][CH2:18][CH3:19])[C:3](OCC)=[O:4].[NH2:20][C:21]([NH2:23])=[S:22].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:18]([O:17][C:9]1[CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=[CH:13][C:8]=1[CH:2]1[S:22][C:21](=[NH:20])[NH:23][C:3]1=[O:4])[CH3:19]
Reactant: CCOC(=O)C(Cl)c1ccc(OCC)cc1OCC
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2SC(=N)NC2=O)c(OCC)c1
Yield: 71.5 %

Procedure:
730 mg of ethyl α-chloro-α-(2,4-diethoxyphenyl)acetate and 380 mg of thiourea, in 7 ml of ethanol, are stirred under reflux for 1 hour. After cooling, the solution is poured in 30 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and distilled to remove the ethyl acetate, whereby 510 mg (74.5%) of 5-(2,4-diethoxyphenyl)-2-iminothiazolidin-4-one is obtained, m.p. 179°-181° C. (hemihydrate).