Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]/[CH:17]=[CH:18]/[O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[O:26]CC4C=CC=CC=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[ClH:39]>C(O)(=O)C>[ClH:39].[F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[OH:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(O/C=C/CCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 75 °C

Procedure:
The mixture of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butenyl]oxy]-4-benzyloxyphenyl]ethanone (5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml) was heated at 75° C. for 2 hours. At the end of reaction, the solvent was reduced to about 20 ml on a rotary evaporator. The solution was poured into ice water (350 ml) and extracted with dichloromethane (3×250 ml). The dichloromethane solution was washed with brine and dried over Na2SO4. A solid formed on concentration of the solvent. This was collected by filtration (3.4 g). Recrystallization from hot methanol (40 ml) gave 1.82 g of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanone hydrochloride as white crystals, 37.5%, m.p.=208°-210° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[O:14][CH2:13][CH2:12][O:11][C:8]=3[CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2cc3c(cc12)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ncnc2cc3c(cc12)OCCO3
Temperature: 125 °C
Yield: 94 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one (1.114 g, 5.46 mmol) and POCl3 (10 mL) in toluene (10 mL) was heated at 125° C. for 5 hours to afford 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline as a solid (1.143 g, 94%). 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 4.46 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc[nH]n1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=Nc2cc[nH]n2)C=C(C(C)(C)C)C1=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A mixture of 5.3 g of 2,6-di-tert-butyl-1,4-benzoquinone, 2.1 g of 3-aminopyrazole and 16 drops of acetic acid was heated with stirring at 110° C. for 15 minutes. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent: diethyl either-chloroform=1:20), giving 5.5 g of 2,6-di-tert-butyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 34a) as a pale red solid.
Reaction SMILES: [Li+].[OH-].N(C1C=C(C=CC=1)C([NH:12][CH2:13][C:14]([NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=O)C(N)=N.FC(F)(F)C(O)=O>O>[NH2:12][CH2:13][C:14]([NH:16][CH:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=N)N)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CC(NC(=O)CN)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiOH x H2O (775 mg) was added to a solution of ethyl 3-{2-[(3-(guanidino)benzoyl)amino]acetamido}-3-phenyl-propanoate from II.1-E (2.0 g) in 100 ml of water and the mixture was stirred at room temperature for 1 h. It was then neutralized with trifluoroacetic acid and concentrated. After purification by HPLC, a white solid was obtained (yield: 1.4 g).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][C@H:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pt]=O>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@H:6]1[CH2:7][CH2:8][C@H:4]([NH2:1])[CH2:5]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1

Procedure:
A mixture of (±)-trans-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane (400 mg, 1.66 mmol) (from Example 9b supra) and platinum oxide (38 mg, 0.17 mmol) (Aldrich) in ethanol (6 mL) was stirred under 1 atmosphere of hydrogen pressure for 2 hours. The reaction mixture was then filtered. The solids were washed with tetrahydrofuran (approx. 40 mL) and the combined organic layer was evaporated under reduced pressure to give (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine as a colorless liquid. (Yield 270 mg, 76%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2].[Br:31]Br>CC(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=3)=[C:17]([Br:31])[C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)cc2n(C)c1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(Br)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Intermediate 1, 170 mg, 0.40 mmol) in HOAc (3 mL) was added Br2 (76.6 mg, 0.48 mmol). The reaction was stirred at RT for 2 h then diluted with EA (10 mL) and water (5 mL). The organic layer was washed with water (3×20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 3-(7-bromo-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (150 mg, 74.4% yield) as a yellow oil. LCMS: MH+ 504 and TR=1.739 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15](C3C=CC=CC=3)[CH2:14]2)[N:10]=[C:9]1SCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:38].[I-].N.CO>CO.CCO>[NH2:38][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:13])[C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[O:16][CH:15]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)[N:10]=1
Reactant: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Solvent: CO
Product: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 0.10 mmol) in MeOH/EtOH (1:1, 2 mL) in a 10 mL CEM microwave test tube was added NH4I (50 mg, 0.34 mmol) and NH3/MeOH (7 N, 2 mL). The resulting mixture was heated in a CEM microwave reactor at 120° C. for 60 min. The cooled mixture was concentrated in vacuo and the residue was purified by reversed phase. HPLC to give 2′-amino-1′-benzyl-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (17.3 mg, 34%) as a TFA salt. MS m/z 462 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)=O.C([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])C>C1C=CC=CC=1.O.[Zn].[Hg](Br)Br>[CH3:20][C:19](=[CH:1][C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[C:18]([OH:22])=[O:17]
Reactant: Cc1cc(C=O)sc1-c1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: Br[Hg]Br
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Product: CC(=Cc1cc(C)c(-c2ccccc2)s1)C(=O)O

Procedure:
A mixture of 2-formyl-4-methyl-5-phenylthiophene (20.2 g, 0.1 mol) and ethyl-2-bromopropionate (0.12 mol, 15.5 mL) was added to a suspension of Zn (7 g, 0.1 mol) in 150 mL of benzene with a catalytic amount of HgBr2. The resulting mixture was refluxed under stirring while all amount of Zn will not be dissolved, and subsequently dissolved in water. The organic layer was isolated, washed with a 10% aq. solution of HCl, dried over MgSO4 and evaporated off to dryness. The residue, corresponding to 2-methyl-3-(4-methyl-5-phenyl-2-thienyl)ethyl acrylate, was used without further purification in the synthesis of the related acid. In fact, it was added to a 30% aq. solution of sodium hydroxide in 100 mL of ethanol and refluxed for 2 h. The resulting reaction mixture was diluted in water, acidified and filtered. The precipitate was dried under P2O5. Yield 16.7 g (65%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[NH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Cc1c[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 90 %

Procedure:
3-(3-Methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXXI (656 mg, 90% yield) was prepared from 3-methyl-5-bromoindole using the procedure described above for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (see Example 14).
Reaction SMILES: C(N1CC[C@H](N)C1)(OCC1C=CC=CC=1)=O.[CH3:17][O:18][C:19](=[O:41])[CH2:20][N:21]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1>>[CH3:17][O:18][C:19](=[O:41])[CH2:20][N:21]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:22]1[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: COC(=O)CN(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Product: COC(=O)CN(C1CCCCC1)C1CCNCC1

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 1 using methyl{cyclohexyl[1-(BOC)piperidin-4-yl]amino}acetate prepared in Step A.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1CCCCC1.C(OCC)(=O)C>[Pt].C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc([N+](=O)[O-])c1Cl
Agent: [Pt]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1cccc(N)c1Cl
Reaction time: 12 h

Procedure:
At room temperature, 50 mg of platinum on carbon (5%) were added to a solution of 200 mg (0.71 mmol) of tert-butyl(2E)-3-(2-chloro-3-nitrophenyl)prop-2-enoate in 10 ml of ethyl acetate, and the mixture was hydrogenated at atmospheric pressure for 12 hours. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC. This gave 115 mg (0.62 mmol, 64% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[O-:17][C:18]#[N:19].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([N:19]=[C:18]=[O:17])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: Cc1ccc(C(=O)NC(Cl)C(Cl)(Cl)Cl)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC(N=C=O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 60.7 %

Procedure:
A stirred solution of Example 37D (1.00 g, 3.32.00 mmol) in acetone (20 mL) at ambient temperature was treated with potassium cyanate (1.60 g, 16.0 mmol). The reaction mixture was stirred for 12 hours, concentrated, and the crude residue was purified by flash chromatography (elution with 50% ethyl acetate/hexanes) to provide 620 mg of the desired product as an off-white solid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CCCCCCCCCCCC>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([N:7]([C:8]5[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=5)[C:4]5[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc(C)cc5)cc4)cc3)cc2)cc1
Temperature: 205 °C
Reaction time: 30 h
Yield: 65.5 %

Procedure:
Di-p-tolylamine (12.8 g (0.065 mol)), 14.0 g (0.029 mol) of 4,4″-diiodo-p-terphenyl, 4.7 g (0.034 mol) of anhydrous potassium carbonate, 0.51 g (0.008 mol) of copper powder and 30 ml of n-dodecane were mixed, and heated up to 200 to 210° C. while introducing nitrogen gas, followed by stirring for 30 hours. After the termination of the reaction, the reaction product was extracted with 500 ml of toluene, and insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluent: toluene:hexane=1:2) to obtain 11.8 g of N,N,N′,N′-tetra-p-tolyl-4,4″-diamino-p-terphenyl (comparative compound No. 1) (yield: 65.7%, melting point: 232.5 to 233.5° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:17]([O:19]CC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Cl>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14]/[C:15](/[C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:16]/[C:17]([OH:19])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2C/C(=C/C(=O)O)c2ccc(F)cc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)but-2-enoate (100 mg, 0.246 mmol) was dissolved in NMP (1 mL). Powdered KOH (100 mg) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to RT and acidified with conc. HCl (pH 5-6). The product was isolated by reverse phase chromatography. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.40 (d, 1H), 7.18 (m, 3H), 7.05 (m, 1H), 6.90 (m, 2H), 6.10 (s, 1H), 5.90 (m, 1H), 5.70 (m, 1H), 4.50 (m, 2H), 4.22 (m, 2H), 3.70 (m, 2H), 3.0 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C(O[C:6](=[O:30])[CH:7]([CH2:28][CH3:29])[CH2:8][C:9](=[O:27])[C@@H:10]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:11])(C)(C)C.C(OC(=O)C(Br)CC)(C)(C)C.C[C:43]([CH:45]([N:47](CC1C=CC=CC=1)[CH2:48][C:49]1C=CC=CC=1)C)=O.NO>>[CH2:45]([N:47]([CH2:48][CH3:49])[C:6](=[O:30])[CH:7]([CH2:28][CH3:29])[CH2:8][C:9](=[O:27])[C@@H:10]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:11])[CH3:43]
Reactant: CC(=O)C(C)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCC(CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CCC(Br)C(=O)OC(C)(C)C
Agent: NO
Product: CCC(CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1)C(=O)N(CC)CC

Procedure:
Examples 10 and 11 provide a detailed description for the preparation of (5S)-5-(N,N-dibenzylamino)-2-ethyl-4-oxo-hexanoic acid-tert-butyl ester from tert-butyl-2-bromobutyrate and α-(N,N-dibenzylamino)ethyl methyl ketone. This compound is reduced to the corresponding amino alcohol as described in detail above.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:24][C:25]([OH:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=3[OH:17])[NH:8]2)=[CH:4][C:3]=1[C:28]#[N:29].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:24][C:25]([OH:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=3[OH:17])[NH:8]2)=[CH:4][C:3]=1[C:28](=[NH:29])[NH:30][OH:31]
Reactant: NO
Reactant: N#Cc1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Solvent: CCO
Product: N=C(NO)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl

Procedure:
A solution of the cyano indole (17) (0.365 gr, 0.91 mmol) from above in dry EtOH (5 ml) was treated with an excess of Hydroxylamine (5 ml of 50 wt. % solution in water). The resulting reaction mixture was refluxed for 10 h. The solvent was removed by rotary evaporation, the residue was azeotroped with toluene to yield the title title compound (0.3-0.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.I[CH2:24][CH2:25][OH:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH2:24][CH2:25][OH:26])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccn(CCO)c(=O)c1

Procedure:
The title compound, orange gum, MS: m/e=354.2, 356.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)N2CCOCC2)[nH]n1
Yield: 33 %

Procedure:
As described for example 131 (step 3), 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using morpholine instead of thiomorpholine S,S-dioxide, to the title compound (18 mg, 33%) which was obtained as an off white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1.C(N(CC)CC)C>ClCCl>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH3:60])[C:9]([C:3]5[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=5[Cl:1])=[O:11])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(Cl)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (40 mg, 0.231 mmol) in dichloromethane (2.0 mL) at 25° C. was treated with triphenylphosphine (72 mg, 0.28 mmol). The reaction was cooled to 0° C. and then was treated with N-chlorosuccinimide (37 mg, 0.28 mmol). This mixture was stirred at 0° C. for 5 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and triethylamine (0.04 mL, 0.28 mmol). This mixture was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:99 methanol/dichloromethane) afforded 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (54 mg, 48%) as a white solid: LR-MS for C30H29ClFN7O3 (M+H)+ at m/z=590.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:44])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:44][C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([S:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:11])=[O:10])[CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 211 (1.15 g, 2.29 mmol), NBS (450 mg, 2.52 mmol), and K2CO3 (380 mg, 2.75 mmol) in MeCN (25 mL) was stirred at 40° C. under nitrogen for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, brine, then dried and evaporated. The residue was recrystallised from EtOAc/Et2O/petroleum ether to give tert-butyl 1-bromo-7-[(dibenzylamino)sulfonyl]-2-naphthylcarbamate (212) as colorless crystals: mp 150-151° C.; 1H NMR (CDCl3) δ 8.69 (d, J=1.6 Hz, 1H), 8.57 (d, J=9.1 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.74 (dd, J=8.6, 1.8 Hz, 1H), 7.38 (s, 1H), 7.22-7.15 (m, 6H), 7.12-7.05 (m, 4H), 4.40 (s, 4H), 1.58 (s, 9H); 13C NMR δ 152.4, 139.6, 136.5, 135.5, 132.0, 131.5, 129.7, 128.6, 128.5, 128.1, 127.7, 126.8, 122.1, 121.8, 110.4, 81.8, 50.6, 28.3. Anal. (C29H29BrN2O4S) C, H, N.
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[N:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Ni].CN(C=O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([C:12]2[S:13][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH3:1])=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: CN(c1ccc([N+](=O)[O-])cc1)c1nc(=O)c2cccnc2s1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CN(c1ccc(N)cc1)c1nc(=O)c2cccnc2s1
Yield: 72.2 %

Procedure:
A mixture of 1.505 g (4.79 mmol) of 2-[N-methyl-N-(4-nitrophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one obtained in Example 63, 50 ml of DMF and about 1.5 g of Raney nickel was stirred in an atmosphere of hydrogen for 5 hours. The resulting insoluble matters were then removed by filtration. The resulting filtrate was then concentrated under reduced pressure. The residue was then recrystallized from ethanol to obtain 984 mg of 2-[N-(4-aminophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.