Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12](OCC)=[O:13])=[C:9]([NH:17][C:18]([NH2:20])=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[O:11][C:10]3[C:12]([OH:13])=[N:20][C:18]([OH:19])=[N:17][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1oc(-c2ccccc2)cc1NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc(O)c2oc(-c3ccccc3)cc2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
5-Phenyl-3-ureidofuran-2-carboxylate 41 (125 mg, 1.0 eq) was suspended in methanol (5 ml) and treated with 1.5 M NaOH (1 ml). Reaction mixture was heated to reflux for 90 minutes. Reaction mixture was allowed to cool down to room temperature, and was acidified with 6N HCl up to pH 3. Solid was filtered and dried at 95° C. under high vacuum for 24 h to yield 6-phenylfuro[3,2-d]pyrimidine-2,4-diol (79 mg, 76%) as a beige solid which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH:24]1([C:27]2[CH:28]=[C:29](F)[C:30]([N+:34]([O-:36])=[O:35])=[C:31]([F:33])[CH:32]=2)[CH2:26][CH2:25]1>CN(C)C=O>[CH:24]1([C:27]2[CH:32]=[C:31]([F:33])[C:30]([N+:34]([O-:36])=[O:35])=[C:29]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH:28]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1c(F)cc(C2CC2)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2[N+](=O)[O-])CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 1.51 mmol, 302 mg) in dry dimethylformamide (10 ml), diisopropylethylamine (1 eq., 1.51 mmol, 0.26 ml) and 5-cyclopropyl-1,3-difluoro-2-nitrobenzene (D25, 1 eq., 1.51 mmol, 300 mg) were added at room temperature and the mixture was stirred under argon at 120° C. overnight. The crude mixture was then cooled to room temperature and poured onto water (10 ml). The aqueous solution was extracted with ethyl acetate (3×100 ml) and the organics were combined and washed with water and brine alternately (5×100 ml), dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound which was purified by chromatography (30% ethyl acetate-n-hexane 60%) to yield the title compound; 300 g, 0.79 mmol, 52%, M−−H=378.
Reaction SMILES: C1(S([CH:10]([F:12])[F:11])(=O)=O)C=CC=CC=1.Cl[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16]>CN(C=O)C>[F:12][CH:10]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[F:11]
Reactant: O=S(=O)(c1ccccc1)C(F)F
Reactant: CC[Si](Cl)(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)C(F)F
Reaction time: 4 h
Yield: 50.9 %

Procedure:
Into a mixture of 5 g (26 mmol) difluoromethyl phenyl sulfone (4), 1.9 g Mg turnings (78 mmol) and 150 mL DMF at −40° C., was slowly added 11.8 g (78 mmol) chlorotriethylsilane. The reaction mixture was then stirred at −40° C. to 10° C. during a 4 h period until 19F NMR indicated all of 4 was consumed. Similar work-up as above and fractional distillation gave 2.2 g product 19, b.p. 71° C./56 Torr, yield 51%. 1H NMR (500 MHz, CDCl3): δ0.72 (q, 3JH-H=8.0 Hz, 6H); 1.02 (t, 3JH-H=8.0 Hz, 9H); 5.95 (t, 2JH-F=46.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ0.6 (s, CH2); 6.7 (s, CH3); 124.3 (t, 1JC-F=254.8 Hz). 19F NMR (470 MHz, CDCl3): δ−137.6 (d, 2JF-H=45.8 Hz). 29Si NMR (99 MHz, CDCl3): δ3.3 (t, 2JSi-F=24.8 Hz). GC-MS (m/z): 166 (M+); 115 (Et3Si+); 51 (CF2H+).
Reaction SMILES: [Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2>O1CCOCC1.C(OCC)C>[Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CC#CBr)[C@@H]1CCC2=O

Procedure:
A mixture of 188 mg of 10β-(3-bromo-2-propynyl)estr-4-ene-3,17-dione and 376 mg of dichlorodicyanoquinone in 12.5 ml of dioxane is refluxed for 20 hours. The mixture is cooled and diluted with diethyl ether, then washed with aqueous sodium carbonate solution and dried. The solvent is evaporated and the residue is purified by flash chromatography on silica gel eluting with ethyl acetate:n-hexane 30:70 to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:11]1[CH:7]([C:5]2[S:6][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:28][CH3:27])[CH:34]=3)=[CH:3][CH:4]=2)[CH2:8][C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:10]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(Br)s2)c(F)c1
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: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 8 of Preparation 13, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.5 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:22])[CH2:6][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[N+]=[N-]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH:5]([OH:22])[CH2:6][N:7]([CH2:18][CH:19]([CH3:20])[CH3:21])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)CC(O)CN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)CC(O)CN)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
To a solution of Compound 24 (2.615 g, 8.011 mmol) in EtOH (20 mL) was added Pd(OH)2 /C (1.00 g). The mixture was stirred under hydrogen atmosphere for 1 day at ambient temperature. The mixture was filtered and the filtrate concentrated to yield 2.036 g (85% yield) of a colorless oil. 1H NMR (CDCl3) 0.91 (3H, d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz), 1.91 (1H, m), 2.43 (3H, s), 2.81 (2H, m), 2.88 (1H, dd, J=13.6, 7.3 Hz), 2.95 (1H, dd, J=12.6, 7.3 Hz), 2.99 (1H, dd, J=14.5, 7.3 Hz), 3.14 (1H, dd, J=14.8, 5.3 Hz), 3.75 (1H, m), 7.31 (2H, d, J=8.4 Hz), 7.69 (2H, J=8.4 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:15]1[C:19]([C:20]2[C:21]([O:30][CH3:31])=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=2)[CH:25]=O)=[CH:18][C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]1=2>>[S:15]1[C:19]([C:20]2[C:21]([O:30][CH3:31])=[CH:22][C:23]([O:28][CH3:29])=[C:24](/[CH:25]=[CH:2]/[C:1]([C:4]3[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=3)=[O:3])[CH:27]=2)=[CH:18][C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: CC(=O)c1ccc(SCC(=O)O)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(SCC(=O)O)cc1

Procedure:
The title compound was prepared by condensing (4-acetylphenylthio)acetic acid (Ex-23B) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described in Ex-22. Yellow solid, mp 136–138° C. (dec.). 1H-NMR (DMSO-d6) δ 8.35 (s, 1H), 8.08 (d, J=7.4 Hz, 2H), 8.03 (d, J=16.3 Hz, 1H), 7.93–7.87 (m, 3H), 7.82 (d, J=7.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 2H), 7.37–7.27 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.93 (s, 2H). MS m/z=491 ([M+H]+, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH:29]=[C:30]([CH3:32])[CH3:31]>C(O)C>[CH2:28]([N:33]1[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:37][CH2:38]1)[CH:29]=[C:30]([CH3:32])[CH3:31]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: CC(C)=CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 62 %

Procedure:
A mixture of 6.6 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one, 2.56 g of sodium carbonate and 4.0 g of 1-prenylpiperazine was refluxed in 90 ml of absolute ethanol for 2 hours. Then, the reaction mixture was vacuum filtered while still hot and the filtrate was evaporated to a volume of about 20 ml. The crystallized precipitate was vacuum filtered and the product was crystallized from isopropanol to obtain a 62% yield of 5,11-dihydro-11-[3-(4-prenyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 199°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:9]2)[CH:3]=1>COCCOC.C(OCC)(=O)C.O.[Fe].[Fe](Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Agent: Cl[Fe]Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reaction time: 3 h

Procedure:
0.746 g of 4-bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine obtained in step 13.2 is dissolved in the presence of 6.6 mg (0.052 mmol) of iron (H) chloride in 30 mL of 1,2-dimethoxyethane. The medium is then refluxed for 6 hours. A further 10 mg (0.078 mmol) of iron (II) chloride are then added and the mixture is refluxed again with stirring for 3 hours. The medium is then diluted with 50 mL of ethyl acetate and 50 mL of water. The organic phase is then recovered, dried over sodium sulfate and filtered. 2 g of silica are then added to the filtrate, followed by concentrating under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (85/15). 0.534 g (71%) of expected compound is recovered in the faun of a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](NC(OC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1CCC[N:22]([C:26]([O:28][C:29](C)(C)C)=[O:27])C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]([NH:22][C:26]([O:28][CH3:29])=[O:27])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: COC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
In analogy to the procedure described for intermediate 38A, (rac)-3-amino-1-BOC-piperidine gave the title compound as off-white gum. MS: 258.9 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[CH2:23][NH:24]C(=O)C(F)(F)F)[CH:16]=2)C(=O)C(F)(F)F)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O>CO>[NH2:24][CH2:23][CH:22]=[CH:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[NH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC/C=C/c1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NCC=Cc1cccc(NCC2CCCCC2)c1
Reaction time: 16 h

Procedure:
A mixture of (E)-N-(cyclohexylmethyl)-2,2,2-trifluoro-N-(3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)phenyl)acetamide (0.2 g, 0.45 mmol) and K2CO3 (0.19 g, 1.37 mmol) in MeOH:H2O was stirred at room temperature for 24 h and then at 50° C. for 16 h. The solvent was removed under reduced pressure. Purification by column chromatography (5% to 10% MeOH—CH2Cl2 gradient) gave 3-(3-aminoprop-1-enyl)-N-(cyclohexylmethyl)aniline as pale brown semi-solid. Yield (0.06 g, 54%); 1H NMR (400 MHz, DMSO-d6) δ 6.99 (t, J=8.0 Hz, 1H), 6.54-6.53 (m, 2H), 6.44 (d, J=7.2 Hz, 1H), 6.42 (d, J=16.0 Hz, 1H), 6.22-6.15 (m, 1H), 5.58 (t, J=5.8 Hz, 1H), 3.34 (d, J=5.2 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 1.80-1.77 (m, 2H), 1.70-1.56 (m, 3H), 1.54-1.49 (m, 1H), 1.18-1.12 (m, 3H), 0.97-0.91 (m, 2H); RP-HPLC (Method 4) tR=5.30 min, 96.10% (AUC); ESI MS m/z 245.26 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2OC)[nH]c1N

Procedure:
Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(2-methoxy-phenyl)-ethan-1-one (2-bromo-2'-methoxy-acetophenone; Aldrich; Milwaukee/USA) to form the title compound; m.p.: 128° C.; TLC-Rf =0.25 (hexane/ethyl acetate [2:1]).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](O)(=[O:9])[CH3:8].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:7]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(N)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)C(=O)O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
134 g (1.50 mol) of DL-alanine are introduced into acetic acid and treated dropwise with 230 g (2.25 mol) of acetic anhydride. The mixture is additionally stirred at 100° C. for 2 h to complete the reaction and the solvent is then stripped off in vacuo. The solid obtained is suspended in ethyl acetate and filtered off with suction. For purification, the solid is washed several times with diethyl ether.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:19]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: COc1cc(CCl)nc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(c3ccc(O)cc3)CC2)nc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 58.1 %

Procedure:
A mixture of 4.94 g (14.5 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 3.29 g (14 mmol) of 4-chloromethyl-6-methoxy-2-phenylpyrimidine and 2.00 g (14.5 mmol) of powdered potassium carbonate in 50 ml of absolute N,N-dimethylformamide (DMF) was warmed to 80° C., and 322 mg of powdered K2CO3 were added with stirring under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes, and after a further 60 minutes (total addition of 966 mg (7 mmol) of K2CO3). The mixture was stirred for a further 2.5 hours at 80° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the crystalline residue was mixed with 40 ml of water and 50 ml of CH2Cl2, the pH of the mixture was adjusted to 5-6 using 2N HCl, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue (4.25 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.0 cm, height 23 cm) by elution with CH2Cl2 and CH2Cl2 /C2H5OH mixtures, with increasing C2H5OH content (to a maximum of 4% by volume of C2H5OH). The fractions which were unary according to TLC were combined and crystallized from CH3OH. In this fashion 3.06 g (=58% yield) of 4-(4-hydroxyphenyl)-1-(6-methoxy-2-phenylpyrimidin-4-yl-methyl)piperazine were obtained; melting point 166°-67° C., analysis: C22H24N4O2 (MW 376.46) calc. C 70.19, H 6.43, N 14.88; found C 69.9, H 6.4, N 14.5%.
Reaction SMILES: [CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][N:45]2[CH2:49][C@@H:48]([C:50]3[CH:61]=[CH:60][C:53]4[O:54][C:55]([CH3:59])([CH3:58])[O:56][CH2:57][C:52]=4[CH:51]=3)[O:47][C:46]2=[O:62])=[CH:39][CH:38]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][N:45]4[CH2:49][C@@H:48]([C:50]5[CH:61]=[CH:60][C:53]6[O:54][C:55]([CH3:58])([CH3:59])[O:56][CH2:57][C:52]=6[CH:51]=5)[O:47][C:46]4=[O:62])=[CH:39][CH:38]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Reactant: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)(=O)N(COCC[Si](C)(C)C)C6CCCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (207 mg) in DMF (5 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 24 mg) and the mixture stirred at 20° C. for 15 min. A solution of 2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate [Example 15 i)] (170 mg) in DMF (3 ml) was added and the mixture stirred at 20° C. for 18 h. Phosphate buffer solution (pH 6.5, 15 ml) and water (15 ml) were added and the mixture was extracted with EtOAc. The combined extracts were washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by “Flashmaster” chromatography on silica gel. Elution with EtOAc-cyclohexane (2:3) gave the title compound (125 mg). LCMS RT=4.35 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([OH:29])[CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[N:19][C:18]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]2=3)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:18]2[N:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][C@@H:13]3[CH2:12][O:29]3)[C:17]=2[N:26]=1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In methanol (250 ml) was dissolved (2R)-2-hydroxy-4-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)butyl 4-methylbenzensulfonate (4.30 g, 10.25 mmol), potassium carbonate (1.70 g, 12.30 mmol) was added thereto at room temperature and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure and the residue was diluted with chloroform and washed with water. After drying the resultant over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 2.62 g (quantitative) of the title compound in the form of a yellowish solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>O>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:19]([N:25]([CH:27]([CH3:28])[CH3:29])[CH3:26])=[N:20][CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cnc2N(C)C(C)C)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)N(C)c1ncc(Cl)cc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A 100 mL round bottom flask which contains 2-{[5-chloro-2-(isopropyl-methyl-amino)-pyridine-3-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (351, 270 mg, 0.58 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH (62 mg, 1.48 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 20 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.21 g, 94%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.COC(OC)OC.[BH4-].[Na+]>CO.C1COCC1>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH2:13][NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccc(-c2coc(C3CC3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: COC(OC)OC
Product: Oc1ccc(CCNCc2ccc(-c3coc(C4CC4)n3)cc2)cc1
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzaldehyde (0.318 g, 1.49 mmol) in MeOH (5 ml) was added tyramine (0.215 g, 1.57 mmol) and trimethylorthoformate (1.2 mL, 10.97 mmol). The resulting solid was redissolved in THF (3 ml) and allowed to stir for 12 h. Sodium borohydride (0.15 g, 3.94 mmol) was added and the mixture was stirred an additional 2 h. The reaction mixture was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (MeOH/CH2Cl2, 5:95 to 10:90) to yield 4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenol as a white solid (0.43 g, 85%).