Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.[CH:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[C:28](O)=[O:29])=[CH2:24].CCN=C=NCCCN(C)C.O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][C:28](=[O:29])[C:27]1[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=[C:25]([CH:23]=[CH2:24])[CH:26]=1)[CH:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:5]2
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: C=Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(C(=O)NCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
100 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 120-b) and 65 mg of 3-vinyl-5-nitrobenzoic acid were dissolved in 1 mL of chloroform, and 96 mg of WSC was added thereto, followed by stirring for 30 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 112 mg (yield 74%) of a title compound as a yellow solidified product.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:23])[C:6]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18]C(=O)C)=[CH:12][C:11]=1[CH3:22])([CH3:8])[CH3:7])C>CO>[CH3:2][O:4][C:5](=[O:23])[C:6]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([OH:18])=[CH:12][C:11]=1[CH3:22])([CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)c(OC(C)=O)cc1C
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cc(OC)c(O)cc1C
Temperature: 25 °C
Yield: 75 %

Procedure:
A freshly prepared solution of 91 mg (4 mmol) sodium in 5.4 ml methanol was added within 5 min to an ice cooled solution of 235 mg (0.8 mmol) 2-(4-acetoxy-5-methoxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester in 5.4 ml methanol. The solution was naturally warmed to ambient temperature and after 5 h the solvent was removed under reduced pressure. Ice water/1 M HCl 1/1 was added and the mixture was extracted two times with dichloromethane. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to yield 153 mg (0.6 mmol, 76%) of the title compound as brown oil which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:38])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[C:28]([Cl:37])[CH:27]=2)[C@@H:20]([CH3:39])[C:19]1=[O:40])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-].CO.CC(C)=O>C1COCC1.C1CCCCC1.[OH-].[Na+]>[Cl:37][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:13][CH2:14]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[C:19](=[O:40])[C@@H:20]2[CH3:39])=[O:38])[CH:31]=[CH:30][C:29]=1[O:32][C:33]([F:35])([F:36])[F:34]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CC(C)=O
Solvent: CO
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of 0.200 g (0.34 mmol) of (S)-2-[(S)-4-(3-chloro-4-trifluoromethoxy-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester (example 54) in 1.0 ml of THF was treated with 0.17 ml (0.34 mmol) of LiBH4 (2 M in THF) and 0.027 ml (0.68 mmol) of MeOH (with cooling bath at RT). The reaction was stirred for 2 h at RT, cooled to 0° C. and stopped with 0.1 ml of acetone. The reaction was diluted with 0.3 ml of cyclohexane, 0.9 ml of aqueous 2 N NaOH were added and after 30 min extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after flash silica gel column (dichloromethane/MeOH 98:2 to 9:1) 0.172 g (88%) of the titled compound as white foam. MS: 577.20 (MH+, Cl).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:37]([O:39][C:40]([NH:42][C:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:41])[CH3:38].O.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[OH2:11].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([CH2:14][CH2:15][N:46]2[CH2:45][CH2:44][C:43]([NH:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:48][CH2:47]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Reactant: CCOC(=O)NC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3ccccc3)C(=O)CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1 g of 4-(ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate and 0.7 g of K2CO4 in 3 ml of DMF is heated at 80°-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and stirred for 30 minutes and the precipitate formed is wrung, washed with water and dried under vacuum at 60° C. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/v to 100/4.5; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.52 g of the expected product. M.p.=148°-150° C.
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[S:17][C:18]([CH:23]([CH3:25])[CH3:24])([CH3:22])[C:19](=[O:21])[N:20]=1)C1C=CC=CC=1.I[Si](C)(C)C>C(Cl)Cl>[OH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[S:17][C:18]([CH:23]([CH3:25])[CH3:24])([CH3:22])[C:19](=[O:21])[N:20]=1
Reactant: CC(C)C1(C)SC(N[C@H]2CCCC[C@@H]2OCc2ccccc2)=NC1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(C)C1(C)SC(N[C@H]2CCCC[C@@H]2O)=NC1=O
Temperature: 65 °C

Procedure:
A 5 mL vial was charged with 2-((1S,2S)-2-(benzyloxy)cyclohexylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (0.100 g, 0.28 mmol) and 1 mL of DCM. To this was added iodotrimethylsilane (0.22 g, 1.1 mmol). The vial was sealed and heated at 65° C. for 36 h. The reaction was concentrated and purified by column chromatography (2% to 7% MeOH/DCM) to give 2-((1S,2S)-2-hydroxycyclohexylamino)-5-isopropyl-5-methylthiazol-4(5H)-one as a yellow solid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][OH:24])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].O[C:45]1[CH:46]=[C:47]([C:51]2([O:57][CH3:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:49]3[CH:50]=[CH:45][CH:46]=[C:47]([C:51]4([O:57][CH3:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)[CH:48]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2oc(CO)nc2-c2ccc(F)cc2)cc1
Reactant: COC1(c2cccc(O)c2)CCOCC1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(c2cccc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A solution containing 4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]oxazole from Step 3 (169 mg, 0.487 mmol) in 20 mL of dichloromethane was stirred at 25° C. as triethylamine (136 μL, 0.974 mmol) was added dropwise, followed by the addition of mechanesulfonyl chloride (56 μL, 0.730 mmol). The reaction was stirred for 5 minutes, after which the organic solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo to give a yellow oil which was characterized as the expected mesylate by its NMR spectrum: 1H-NMR (CDCl3, 400 MHz) δ 3.08 (s, 3H), 3.17 (s, 3H), 5.37 (s, 2H), 7.12 (t, 2H, J=8.8 Hz), 7.58 (m, 2H), 7.78 (d, 2H, J=8.8 Hz) and 7.94 (d, 2H, J=8.8 Hz). This material was used without further purification. The mesylate was dissolved in 20 mL of DMF and potassium carbonate (81 mg, 0.584 mmol) was added, followed by the addition of 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (122 mg, 0.584 mmol). The reaction was stirred at 25° C. for 3 days and poured into 100 mL of water. The aqueous solution was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a beige solid. This material was purified by flash chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent to give 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole (185 mg, 71%) as a white crystalline solid: 1H-NMR (CDCl3, 300 MHz) δ 1.90–2.05 (m, 4H), 2.97 (s, 3H), 3.08 (s, 3H), 3.81 (m, 4H), 5.25 (s, 2H), 6.98–7.17 (m, 5H), 7.33 (t, 1H, J=7.7 Hz), 7.60 (m, 2H), 7.78 (d, 2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz) δ −111.6. LRMS m/z 544 (M+Li). HRMS Calc'd. for C29H28NO6FS: 544.1781 (M+Li). Found: 544.1831 (M+Li).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[OH:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c(F)c1F
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)c(F)c1F
Yield: 91.5 %

Procedure:
To 2,3-difluoro-4-methylphenol (1 g, 6.94 mmol) in dichloromethane at 0° C. was added nitric acid 70% (0.7 mL, 7.77 mmol). After 1 h at room temperature the solution was washed with water, dried and evaporated to give 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol, 91% yield) (D44) as yellow solid.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[C:10]([O:17][CH3:18])=[N:11][CH:12]=[N:13][C:14]=1[O:15][CH3:16])[CH:3]=[N:4][O:5][CH2:6][CH3:7].[Cl:19][CH2:20][C:21](Cl)=[O:22].[OH-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([N:8]([C:9]1[C:14]([O:15][CH3:16])=[N:13][CH:12]=[N:11][C:10]=1[O:17][CH3:18])[C:21](=[O:22])[CH2:20][Cl:19])[CH:3]=[N:4][O:5][CH2:6][CH3:7]
Reactant: CCON=CC(C)Nc1c(OC)ncnc1OC
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCON=CC(C)N(C(=O)CCl)c1c(OC)ncnc1OC

Procedure:
12.7 g N-[1-methyl-(ethoxyimino)ethyl]-4,6-dimethoxy-pyrimidine-5-amine and 150 ml dry CH2Cl2 are charged in a sulphonation flask. Thereto are added, dropwise, 6.2 g chloracetylchloride in 25 ml dry CH2Cl2. The reaction temperature rises from 22° to 28°. The reaction mixture is heated under reflux for 2 hours and cooled. Then 10% aqueous NaOH is added, the organic phase partitioned off, dried over Na2SO4 and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:18][C:19]([F:22])([F:21])[F:20])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-])=O>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([O:18][C:19]([F:22])([F:20])[F:21])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N)c2[nH]1
Yield: 94.9 %

Procedure:
A mixture of ethyl 7-nitro-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.06 g), 10% palladium-carbon (50% containing water, 600 mg) and tetrahydrofuran (150 mL) was subjected to catalytic reduction under hydrogen atmosphere at normal pressure. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained crystals were washed with hexane to give the title compound (2.63 g, yield 95%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 190-191° C.
Reaction SMILES: O.C([O:4][C:5]([CH:7]1[CH2:19][CH2:18][C:10]2[N:11]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[S:13][C:9]=2[CH2:8]1)=[O:6])C.[OH-].[Na+]>C(O)(=O)C>[C:15]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:19][CH2:18][C:10]=2[N:11]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(s1)CC(C(=O)O)CC2
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of water, 30 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(II), R1=ethyl, R=—NH—CO—CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30° C.; during the addition the solid gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was dropwise added to pH=4.5-5.5; after approx. 1 hour the precipitated white solid was filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=O)[N:15]3[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[S:35])[N:15]3[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)CCc2ccc(-n3c(C)ccc3C)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)CCc2ccc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (1.6 g, 4.70 mmol) and Lawesson reagent (1.9 g, 4.70 mmol) in toluene (20 mL) was heated to reflux for 2 h. The reaction mixture was cooled to ambient temperature and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-5% EtOAc in petroleum ether) to give ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-thioxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (0.20 g, 12%). 1H NMR (CDCl3, 400 MHz): δ 7.27 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.06 Hz, 1H), 6.82 (s, 1H), 6.58 (m, 1H), 5.91 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.24 (m, 2H), 2.85 (m, 2H), 2.03 (s, 6H), 1.71 (d, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH3:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:8](=[O:9])([O:10][CH2:11][Cl:12])[O:17][C:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)OCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.62 mL pyridine was added dropwise to a solution of 0.77 g chloromethyl chloroformate and 1.32 mL t-BuOH in 60 mL CH2Cl2 cooled in an ice bath under an Ar atmosphere. The reaction was stirred 2 hours at 0° C. then transferred to a separatory funnel. The reaction was washed twice with H2O, once with 10% CuSO4, once with brine and dried with MgSO4. Suction filtration and evaporation provided 0.55 g of desired product which was used without purification.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:8][C:9]([CH2:12][CH2:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH:17]=[C:16]2[C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:10][CH:11]=1)=[O:6]>C1COCC1>[OH:32][C@H:26]([C:23]1[CH:24]=[CH:25][C:20]([C:16]2[C@@H:15]([CH2:14][CH2:13][CH2:12][C:9]3[S:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=3)[CH2:19][CH2:18][CH:17]=2)=[CH:21][CH:22]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCC[C@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC[C@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
LiOH (0.5 mL, 0.5 mmol, 1 M) was added to a THF (1.5 mL) solution of 43 (14 mg, 0.033 mmol). The mixture was stirred overnight at 60° C., allowed to cool to room temperature and then quenched by addition of 1 M HCl (10 mL). The mixture was extracted with CH2Cl2 (3×15 mL) and the combined CH2Cl2 solution was dried (Na2SO4), filtered and evaporated to leave the title compound (13 mg, 0.031 mmol, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1[CH3:21].CN([Si:29](N(C)C(N(C)C)=O)(C)C)C(N(C)C)=O>C1(C)C=CC=CC=1>[SiH4:29].[CH3:9][C:6]1[C:7]([OH:8])=[C:2]([CH3:1])[C:3]([CH3:21])=[C:4]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])[C:5]=1[CH3:10]
Reactant: CN(C)C(=O)N(C)[Si](C)(C)N(C)C(=O)N(C)C
Agent: Cc1c(C)c(C(C)(C)c2ccc(O)cc2)c(C)c(C)c1O
Solvent: Cc1ccccc1
Product: [SiH4]
Temperature: 78 °C

Procedure:
There was added 9.4391 grams (0.03367 mols) of tetramethylbisphenol-A in increments of 4.72 grams, 2.36 grams and 2.35 grams at half hour intervals using 10 ml dry toluene to transfer each addition to 7.82 grams (0.03367 mols) of a 50% by weight toluene solution of bis(trimethylureido)dimethyl silane maintained under a nitrogen blanket at a temperature of 78° C. The final solution had about 27% by weight solids. The temperature of the resulting solution was raised to 120° C. one hour after the final tetramethylbisphenol-A addition to maintain the toluene solution under reflux . The reaction was monitored by GPC. The mixture was refluxed for an additional hour. A poly(tetramethylbisphenol-A monosiloxane) was obtained having a MWw of 17,800. After the removal of some toluene to increase the percent solids level, additional bisuriedo silane was added to provide a 7% excess. The reaction was left at reflux for two hours and an additional 2.35 millimoles of bisuriedo silane was added to provide a 14% excess silane. The reaction was continued for two hours diluted with toluene and then cooled slightly prior to precipitation in isopropanol. There was obtained a polymer having MWw of 56,500 and MWn of 32,900 by GPC.
Reaction SMILES: [CH3:1][Mg]Br.C(O[C:7]([C:9]1([CH2:16][CH2:17][O:18][CH3:19])[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)=[O:8])C.[NH4+].[Cl-]>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][C:9]12[CH2:10][CH2:11][C:12]([CH3:1])([CH2:13][CH2:14]1)[O:15][C:7]2=[O:8]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C1(CCOC)CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCC12CCC(C)(CC1)OC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 1.22 mL) was dissolved in THF (5 mL). The mixture was cooled to 0° C. and a solution of 1-(2-methoxy-ethyl)-4-oxo-cyclohexanecarboxylic acid ethyl ester (350 mg, obtained in example 1, step 2) in THF (5 mL) was added dropwise over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into ice/water and acidified with sat. NH4Cl. The aqueous phase was extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless liquid (67 mg, 22%). 1H-NMR (8, CDCl3): 3.55 (t, 2H); 3.31 (s, 3H); 1.86 (t, 2H); 1.84-1.73 (m, 8H); 1.39 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:39]>ClCCl>[CH2:1]([S:8]([C:9]1[N:14]=[C:13]2[N:15]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(CC)CCN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Solvent: ClCCl
Product: CCN(CC)CCN1C(=O)N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxidation of the 7-benzylthio-3-(2-chlorophenyl)-1-(2-diethylaminoethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was accomplished using 3-chloroperoxybenzoic acid (0.339 g, 1.96 mmol) in dichloromethane with stirring at room temperature for 1 hour. The reaction was quenched with 10% sodium sulfite solution (aq, 5 mL), poured into saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to provide 7-benzylsulfinyl-3-(2-chlorophenyl)-1-(2-diethylamino-ethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].CC(C[AlH]CC(C)C)C.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]
Reactant: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCCC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCCCO
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Compound 47 (50 mg, 0.11 mmol) was dissolved in THF (5 mL) and cooled to 0° C. under nitrogen. DIBAL (1.5 M in hexane, 500 ul, 0.33 mmol) was added drop-wise over several minutes. The ice bath was removed and the stirring reaction allowed to warm to ambient temperature. The reaction was then cooled back to 0° C. and water (10 mL) added dropwise over several minutes. The ice bath was then removed and the reaction was stirred until solids began to form. The solids were filtered and the filtrate washed several times with dichloromethane. The filtrate was concentrated in vacuuo to give 42 mg (98%) of compound 48 as a clear oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (s, 6H), 0.95 (s, 6H), 1.29 (s, 2H), 1.75 (s, 2H), 1.90 (s, 2H), 2.08-2.17 (m, 5H), 2.55 (t, J=7.3 Hz, 2H), 3.72 (t, J=6.3 Hz, 2H), 3.97 (t, J=6.1 Hz, 2H), 6.70 (d, J=9.0 Hz, 1H), 6.91-6.99 (m, 2H), 7.10-7.20 (m, 3H), 7.20-7.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccc(F)cc2c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a mixture of 1-(5-fluoro-2-hydroxyphenyl)ethanone (100 g), methyl bromoacetate (67.6 mL) and N,N-dimethylformamide (500 mL) was added potassium carbonate (135 g), and the mixture was stirred at 50° C. for 2 hr. The insoluble material was filtered off, 1,8-diazabicyclo[5.4.0]undec-7-ene (97.1 mL) was added, and the mixture was stirred at 120° C. for 30 min. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration to give the title object compound (77.9 g, 58%) as a white solid.