Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=O)=O.[O:18]1[CH2:23]COC[CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.O>[CH3:19][O:18][CH2:23][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C1COCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCCCCCC
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 95 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a mixture of 4-nitrophenyl trifluoromethanesulfonate (30 mg, 0.11 mmol) and 1,4-dioxane (3 ml) were added water (0.3 ml), cesium carbonate (0.11 g, 0.34 mmol), potassium methoxymethyl trifluoroborate (17 mg, 0.11 mmol),palladium (II) acetate (1.3 mg, 0.0056 mmol) and tri-o-tolylphosphine (8.5 mg, 0.028 mmol). Then, the reaction mixture was stirred at 95° C. (external temperature) for 4 hours. After the reaction mixture was cooled at room temperature, water and heptane were added to the mixture, and the organic layer was separated. The organic layer was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (13 mg, 0.078 mmol, 68%).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]([O:17]C(=O)C)[CH2:10][O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].C(Cl)(Cl)Cl.Cl.C(O)C>CO.C(O)C.O>[N+:1]([C:4]1[S:8][C:7]([CH:9]([OH:17])[CH2:10][O:11][CH2:12][CH2:13][N:14]([CH3:15])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN(C)CCOCC(O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
In 10 ml of methanol was dissolved 320 mg of 1-(5-nitro-2-thienyl)-1-acetoxy-2-[2-(N,N-dimethylamino)-ethoxy]ethane. To the solution was added 1.27 ml of a 1N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 40 ml of chloroform and 40 ml of water. The organic layer was separated and 30 ml of water was added thereto. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of chloroform was added thereto. The resulting mixture was adjusted to pH 11 with a 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 3 ml of methanol and 1 ml of a 5N dry hydrogen chloride-ethanol solution. The solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 5 ml of ethanol. The resulting crystals were collected by filtration and dried to obtain 170 mg of 1-(5-nitro-2-thienyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol (compound No. 405).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:52]=[C:53]([CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=1)[C:54]([OH:56])=O.[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:54](=[O:56])[C:53]1[CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=[C:51]([O:50][CH2:49][CH2:48][CH2:47][CH2:46][O:45][CH3:44])[CH:52]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1
Reactant: COCCCCOc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: COCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-(4-methoxybutoxy)-5-(2-oxopyrrolidin-1-yl)benzoic acid (D59) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:12][CH2:13][CH2:14][C:10]=2[CH:9]=[C:5]2[O:6][CH2:7][CH2:8][C:4]=12)=[O:2].[OH-:15].[Na+]>[Ag-]=O>[O:6]1[CH2:7][CH2:8][C:4]2=[C:3]([C:1]([OH:15])=[O:2])[C:11]3[O:12][CH2:13][CH2:14][C:10]=3[CH:9]=[C:5]12
Reactant: [OH-]
Reactant: O=Cc1c2c(cc3c1OCC3)OCC2
Agent: O=[Ag-]
Agent: [Na+]
Product: O=C(O)c1c2c(cc3c1OCC3)OCC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Formyl-2,3,6,7-tetrahydro-benzo[1,2-b; 4,5-b′]difuran (0.25 mmol; Lit.: A. P. Monte, D. Marona-Lewicka, M. A. Parker, D. B. Wainscott, D. L. Nelson, D. E. Nichols J. Med. Chem., 1996, 39, 2953-2961) is added to a stirred suspension of silver(I) oxide (0.375 mmol) in an aq. NaOH solution (5%, 0.20 mL). The mixture is stirred for 5 h, filtered and washed with water (2.0 mL). The filtrate is cooled to 0° C. and made acidic by dropwise addition of hydrochloric acid (25%). The obtained suspension is filtered off and washed with ice-cold water and heptane. The residue is dried in vacuo to give the desired acid as a grey powder which is used without further purification. LC-MS (basic): tR=0.20 min; [M−H]−=205.2.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)Cc1nnc(N)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 43 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (1.01 g, 2.94 mmol) in pyridine (10 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (500 mg, 2.67 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 108-109° C., in 43% yield (570 mg, 1.15 mmol); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 1.24-1.34 (m, 21H), 1.55-1.66 (m, 2H), 2.63 (t, 2H, J=7.2 Hz), 3.88 (s, 2H), 4.25 (q, 2H, J=7.5 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.1, 22.7, 29.3, 29.5, 29.6, 29.7, 31.2, 31.9, 35.9, 38.1, 61.9, 126.7, 128.4, 138.8, 147.2, 152.1, 168.3, 170.3; MS (LCQ, ESI+) Calcd for C24H38N3O4S2 496.2, found 496.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H38N3O4S2 496.2304, found 496.2295 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11]([O:14][Si:25]([CH3:28])([CH3:27])[CH3:24])=[CH:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: C[Si](C)(C)Cl
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21
Product: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(C(F)(F)F)ccc21

Procedure:
Following the general procedure of Part A, 2.4 g of 7-trifluoromethyl-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one was reacted with trimethylchlorosilane. The filtrate was evaporated, the residue was dissolved in CFCl3 and the CFCl3 was removed by evaporation to give 7-trifluoromethyl-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepin which was again dissolved in CFCl3 and reacted with trifluoromethyl hypofluorite to give 7-trifluoromethyl-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one whose measured mass spectrum was m/c 336.0859; Calculated for C17H12ON2F4 : 336.0885.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=O.Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24].C(=O)(O)[O-].[Na+].C(#N)C>C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:15]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1
Yield: 40.2 %

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-4'-methoxyacrylophenone (prepared as described in Example 8) and 9.2 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. Evaporation of the solvent in vacuo gave a solid which was treated with saturated sodium bicarbonate solution, then washed with water and filtered to give colorless crystals. This material was treated with hot acetonitrile and collected by filtration. Recrystallization from ethanol gave 6.1 g of the desired product as yellow crystals, mp 246°-249° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (750 mg), 1 N aqueous sodium hydroxide solution (3 ml), ethanol (3 ml), and tetrahydrofuran (3 ml) was stirred at room temperature for one hour. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (610 mg, yield: 90%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 110–111° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:41]([NH2:40])=[O:42])=[CH:35][CH:34]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNC(N)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of (2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (50 mg, 0.10 mmol) in DCM (1 mL) was added trimethylsilyl isocyanate (23 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 0.2 mL of water and concentrated under reduced pressure. The crude residue was purified by preparatory HPLC to afford the product (9 mg, 17%).
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C:3](OCC)=[O:4].FC(F)(CCC1C=CC=CC=1)CO>>[F:1][C:2]([F:15])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1cccc(C)c1
Agent: OCC(F)(F)CCc1ccccc1
Product: Cc1cccc(C(F)(F)CO)c1

Procedure:
Obtained from Intermediate 28 (9.5 g, 40 mmol) by the procedure described in Intermediate 2. The title compound was obtained (5.55 g, 80%) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[S:17](=[O:28])(=[O:27])[N:16]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=3[S:17](=[O:27])(=[O:28])[N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C2Cl
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Yield: 39 %

Procedure:
A mixture of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (318 mg, 1.31 mmol) and 3-chloro-6-nitrobenzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (357 mg, 1.45 mmol) in 15 ml acetonitrile was stirred under dry nitrogen at room temperature then heated to reflux for several minutes until the material dissolved. The solvent was removed under reduced pressure and the residue recrystallized from ethanol and triturated with hot ethanol, yielding 250 mg (39%) of the title compound as the hydrochloride salt, m.p. 235°-242° C. IR(KBr) 1620, 1345, 1300, 1160 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([NH:26]CC5C=CC(OC)=CC=5)[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([NH2:26])[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)ncnc3cn2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.3 %

Procedure:
To a stirred heterogeneous mixture of compound 211 (2.27 g, 4.48 mmol) and DCM (45 ml) was added trifluoroacetic acid (3.45 ml, 44.8 mmol), followed by anisole (0.99 ml, 8.96 mmol), and the mixture was stirred further at room temperature for 5 days. It was poured into petroleum ether (500 ml) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 ml). To the solid left behind was added 5M NH3 (80 ml) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 ml), petroleum ether-ethyl acetate=3:1 (3×20 ml), and dried to give N4-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]pyrimidine-4,6-diamine (220) (1.68 g, 97%), mp 241-244° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.67 (s, 1H), 8.30 (s, 8.27 (br s, 1H), 8.15 (s, 1H), 7.75-7.68 (m, 2H), 7.41-7.33 (m, 14, 7.18 (s, 1H), 7.14-7.01 (m, 3H), 6.20 (s, 2H), 5.69 (s, 2H). Anal. Calcd for C21H16FN7.1.5H2O: C, 61.16; H, 4.64; N, 23.77. Found C, 61.23; H, 4.71; N, 23.87.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][OH:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]3[CH2:35][CH2:34][CH2:33][CH:32]3[CH2:36][OH:37])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: OCC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCCC3CO)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 51 mg of pyrrolidin-2-ylmethanol and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[C:9]3[CH2:18][C:19](=[O:22])[CH2:20][CH2:21][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>O>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[C:9]3[CH2:18][CH:19]([OH:22])[CH2:20][CH2:21][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2c(c(=O)c3cccnc3n2-c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)CCC(O)C2
Reaction time: 0.25 h

Procedure:
Reduce 6,8,9,10-tetrahydro-10-phenylbenzo[b] [1,8]naphthyridin-5,7-dione (2 mmol) with sodium borohydride (50 mg) in a solvent of ethanol (30 ml) and water (0.25 ml). After 15 minutes, pour the reaction mixture over ice and collect the resulting precipitate on a filter. Reserve the precipitate, and extract the aqueous filtrate with chloroform. Dry the extracts, evaporate the chloroform, and combine the residue with the reserved precipitate to give the product, 10-phenyl-7-hydroxy-6,7,8,9-tetrahydro-benzo[b] [1,8]naphthyridin-5(10H)-one, m.p. 283°-286° C. after crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([O:26][CH2:30][CH3:31])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Example 68 (60 mg, 0.14 mmol) in DMF (1 mL) was added bromoethane (152 mg, 1.4 mmol) and NaH (6 mg, 0.14 mmol) and the suspension was stirred for 1 h at rt. The reaction was quenched by adding 1N HCl and water. The reaction was diluted with EtOAc, washed with a saturated aq NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 85% CH2Cl2 in hexane to afford the title compound. (LC-2) HPLC/MS: 462.2 (M+1), 464.2 (M+3); Rt=4.51 min
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:17][C:18]2[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=2)[C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:17][C:18]2[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=2)[C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(Nc1cccc(C(=O)c2cc(CCCC(=O)OCC)c3ccccn23)c1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCC(Nc1cccc(C(=O)c2cc(CCCC(=O)O)c3ccccn23)c1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indolizin-1-yl]butyrate (117 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added 1N aqueous solution of sodium hydroxide (1 ml). The mixture was stirred at room temperature for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indolizin-1-yl]butyric acid (98 mg) as powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C@@H:6]([O:8][C:9]2[CH:32]=[CH:31][C:12]3[C:13]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:17])[O:16][C:11]=3[C:10]=2[CH3:33])[C@H:5]([OH:34])[C@H:4]([OH:35])[C@H:3]1[O:36][CH3:37].C(N(C(C)C)CC)(C)C.N1C=CN=C1.[CH2:53]([Si:55]([CH2:59][CH3:60])([CH2:57][CH3:58])Cl)[CH3:54].P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[CH3:38][C:2]1([CH3:1])[O:7][C@@H:6]([O:8][C:9]2[CH:32]=[CH:31][C:12]3[C:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:17])[O:16][C:11]=3[C:10]=2[CH3:33])[C@H:5]([OH:34])[C@H:4]([O:35][Si:55]([CH2:59][CH3:60])([CH2:57][CH3:58])[CH2:53][CH3:54])[C@H:3]1[O:36][CH3:37]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2ccc(O[C@@H]3OC(C)(C)[C@H](OC)[C@@H](O)[C@H]3O)c(C)c2oc1=O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2ccc(O[C@@H]3OC(C)(C)[C@H](OC)[C@@H](O[Si](CC)(CC)CC)[C@H]3O)c(C)c2oc1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g of a solution from stage A in 500 ml of methylene chloride is agitated under arcon at ambient temperature. 42 ml of diisopropylethylamine and 9.66 g of imidazole are added. The solution is agitated for 15 minutes or cooled down to 0° C., 20.64 ml of triethylchlorosilane is added dropwise over 30 minutes, and agitation is carried out for 2 hours at 0° C. The reaction medium is poured into a molar solution of sodium dihydrogen phosphate. Extraction is carried out with methylene chloride followed by drying and evaporating to dryness. 66.27 g of product is recovered that is purified on silica eluting with a methylene chloride mixture at 0.75% of acetone. When the product is nearly isolated,, eluting is carried out with a methylene chloride solution at 1% of acetone. 41.04 g of sought product is obtained after saponification in a hexane/ethyl acetate mixture (9-1).