Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH:21]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCCCCC>C1(C)C=CC=CC=1>[CH:21]1([NH:29][C:30]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C=NC1CCCCCCC1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NC2CCCCCCC2)CC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (0.30 g, 1.07 mmol) in anhydrous toluene (5 mL), cyclooctyl isocyanate (0.177 g, 1.15 mmol) was added and the mixture was heated at reflux until all solid dissolved. The solution was allowed to cool slowly to room temperature. Hexane was added and the resulting oil was extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to afford 0.40 g (84%) N-cyclooctyl-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazine-carboxamide D3 as a colourless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:18])[CH2:12][NH:13][CH2:14][CH:15]([CH3:17])[CH3:16].[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[Br:19][CH2:20][C:21]([N:13]([CH2:12][C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:22]
Reactant: CC(C)CNCC(=O)N1CCc2ccccc2C1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CBr
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a stirred solution of 1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-isobutylamino-ethanone (0.45 g, 1.8 mmol) in THF (4.0 mL), a solution of bromoacetyl bromide (0.32 mL, 3.6 mmol) in 4.0 mL THF was added dropwise at −78° C., under argon. After 3 h (the temperature gradually rose to 10° C.) the reaction was concentrated and the remaining residue was diluted with methylene chloride and saturated NaHCO3. The layers were separated and the organic phase was washed with brine and then dried (MgSO4). Filtration and concentration gave the crude product which was purified via silica gel flash chromatography (0-5% MeOH/methylene chloride, 30 mL/min.) to give 0.34 g (51%) of 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2)C(CC2CCCC2)NC(C(=O)O)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.5 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=O)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[S:38])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2-c2ccc(F)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=S)c2-c2ccc(F)cc2)cc1
Yield: 171 %

Procedure:
A solution of 3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one(0.45 g, 1.14 mmol) from Example 1 and Lawesson's reagent(0.23 g, 0.57 mmol) in toluene(10 ml) was refluxed for 1 hour. The resulting mixture was concentrated and subjected to flash chromatography using a mixture of hexane:ethyl acetate:dichloroethane(1:1:1) as an eluant to yield the title compound as a deep green solid(0.4 g, 85%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCOCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: NC(=O)C[C@@H](N)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N[C@H](CC(N)=O)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
D-asparagine (13.2 g, 100.0 mmol) is dissolved in dioxane (75.0 mL) and water (125.0 mL), triethylamine (21.0 mL, 150.0 mmol) is added, and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (22.7 g, 110.0 mmol) over 10 minutes. The reaction is warmed to room temperature and stirred for 3 days. The precipitate is then filtered off, the filtrate is acidified to pH=~4, and extracted well with ethyl acetate. A first crop of pure product precipitates from the ethyl acetate and is collected by filtration. A second crop is obtained by evaporating off the ethyl acetate, and rinsing the solid obtained with water to remove inorganic salts. The two crops are combined to give N-[4-methoxybenzenesulfonyl]-(D)-asparagine.
Reaction SMILES: CC1(C)[O:7][C@H:6]2[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11][C@@H:5]2[CH2:4][O:3]1.Cl>CO>[OH:3][CH2:4][C@@H:5]1[C@@H:6]([OH:7])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@H]2OC[C@H](O)[C@H](O)[C@@H]2O1
Agent: Cl
Solvent: CO
Product: OC[C@H]1OC[C@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of (−)-(4aR,7S,8S,8aS)-2,2-dimethyl-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (20 mg, 0.09 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature and concentrated in vacuo.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][O:19][CH:20]3[CH2:25][N:24]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH2:23][CH:22]([OH:36])[CH:21]3[C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:54]=[CH:53][C:47]5[N:48]([CH3:52])[CH2:49][CH2:50][O:51][C:46]=5[CH:45]=4)=[CH:39][CH:38]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O[CH2:65][CH2:66][N:67]([CH3:78])[S:68]([C:71]2[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][CH:72]=2)(=[O:70])=[O:69])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][O:19][CH:20]3[CH2:25][N:24]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:27])=[O:28])[CH2:23][CH:22]([O:36][CH2:65][CH2:66][N:67]([CH3:78])[S:68]([C:71]4[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][CH:72]=4)(=[O:70])=[O:69])[CH:21]3[C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:54]=[CH:53][C:47]5[N:48]([CH3:52])[CH2:49][CH2:50][O:51][C:46]=5[CH:45]=4)=[CH:39][CH:38]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)CC(O)C3c3ccc(Oc4ccc5c(c4)OCCN5C)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)CC(OCCN(C)S(=O)(=O)c4ccc(C)cc4)C3c3ccc(Oc4ccc5c(c4)OCCN5C)cc3)cc21
Temperature: 25 °C

Procedure:
95 mg of sodium hydride dispersion (60%) are added to a solution of 145 mg of 5-[4-(3-methoxypropyl)3,4 -dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(4-methyl-3,4-dihydro-2 H-benzo[1,4]oxazin-7-yloxy)phenyl]-1-(toluene-4-sulphonyl)piperidin-3-ol and 740 mg of 2-[methyl(toluene-4 -sulphonyl)amino]ethyl toluene-4-sulphonate in 5 ml of tetrahydrofuran while stirring at room temperature. The reaction mixture is stirred at 45° C. for 72 hours. The mixture is poured into 1M aqueous sodium bicarbonate solution (5 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed successively with water (2×10 ml) and brine (1×10 ml), dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO2 60F). Rf=0.08 (EtOAc/heptane 1:1); Rt=5.83.
Reaction SMILES: [CH:1](=[N:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:7]1=[O:29])[CH2:2][CH2:3][CH3:4].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:7]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 249A (0.040 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and washed with water (2×5.0 ml) and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.17 Hz, 3 H) 1.48 (m, 4 H) 2.77 (m, 2 H) 5.90 (t, J=6.99 Hz, 1 H) 7.07 (m, 1 H) 7.27 (m, 2 H) 7.58 (m, 3 H) 7.66 (d, J=8.09 Hz, 1 H) 8.08 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 411 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(NC(=O)C(CC)c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of 2-(4-methoxyphenyl)butanoic acid (135 mg, 0.70 mmol) and ethyl 2-aminothiazole-5-carboxylate (100 mg, 0.58 mmol) in DMF were added DIEA (112 mg, 0.87 mmol) and HATU (264 mg, 0.70 mmol). The reaction was stirred at room temperature for 4 hrs and partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified by biotage column chromatography to afford ethyl 2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxylate (163 mg).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:10][CH:9]=2)[O:4]C1.O.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[OH:23][CH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH:5]=[O:4])=[CH:9][CH:10]=1)[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CC(O)c1ccc(C2OCC(C)(C)CO2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(O)c1ccc(C=O)c2ccccc12
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 1-[4-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-naphthyl]-3-methyl-1-butanol (1.76 g, 5.35 mmol) in THF (10 mL) was added water (1 mL) and conc. HCl (1 mL). The solution was stirred at room temp. for 16 hours, diluted with NaHCO3-solution (20 mL), and extracted with ether (3×30 mL). The combined organic extracts were dried and concentrated. Flash chromatography (silicagel, hexanes:ethyl acetate, 4:1) provided 900 mg (70%) colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([O:23]C)=[O:22])[N:4]=1)#[N:2].[OH-].[Na+].C1COCC1.Cl>O.CCOC(C)=O.CO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([OH:23])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (500 mg, 1.56 mmol) and NaOH (375 mg, 9.38 mmol) were dissolved in H2O (13 mL), THF (13 mL) and MeOH (13 mL). After stirring for 2 hours at room temperature, H2O (30 mL) and EtOAc (30 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 3. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated to give 300 mg of the title compound. MS: (−) m/z 305.26 (M−1).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30]P(=O)(OCC)OCC)=[N:27]2)=[CH:22][CH:21]=1.C=O>O1CCCC1>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH2:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)NC(C)C
Reactant: CCOP(=O)(Cc1ccc2ccc(Cl)cc2n1)OCC
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2ccc(Cl)cc2n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) in tetrahydrofuran (15.0 ml) at −10° C. under nitrogen was treated dropwise with a 2.5 M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol). After stirring below 0° C. for 30 min the pale yellow solution was cooled to −20° C. and a solution of diethyl 7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) in tetrahydrofuran was added dropwise. The resulting dark green solution was stirred below 0° C. for 1 h, cooled to −10° C. and treated with paraformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15 min after which the cooling bath was removed and the mixture was stirred at 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (3×200 ml), dried (Na2SO4) and the solvent was removed in vacuo to give a dark brown solid. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:19) provided the title compound (1.80 g, 59%) as pale yellow crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as cream crystals, m.p. 79.7-80° C. (Found: C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C11H8ClN requires C, 69.67; H, 4.25; N, 7.39; Cl, 18.69%); νmax (nujol)/cm−1 1628, 1609; δH (270 MHz) 5.67 (1H, dd, 2′-H, 3J2′,1′=10.89, 2J2′,2″=1.0 Hz); 6.29 (1H, dd, 2″-H, 3J2″,1′=17.7, 2J2″,2′=0.8 Hz); 7.02 (1H, dd, 1′-H, 3J1′,2″=17.5, 3J1′,2′=10.9 Hz); 7.42 (1H, dd, 7-H, Jo=8.8, Jm=2.1 Hz); 7.53 (1H, d, 3-H, Jo=8.9 Hz); 7.66 (1H, d, 5-H, Jo=8.9 Hz); 8.03 (1H, d, 4-H, Jo=8.3 Hz); 8.05 (1H, s, 8-H). δc (67.8 MHz) 118.6 (2′-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0 (4-C); 137.5 (1′-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fall in the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M+), 165.0, 163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCC2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 395.18 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]2[C:5]=1[C:6](=O)[N:7]=[CH:8][NH:9]2)[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:4]=2[O:3][CH2:1][CH3:2])[N:9]=[CH:8][N:7]=1
Reactant: CCOc1cc(OC)cc2[nH]cnc(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1cc(OC)cc2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 5-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (285 mg, 1.29 mmol) in POCl3 (10 mL, 107 mmol) was treated with 1 drop of DMF and stirred at 100° C. for 1 hour before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate), concentrated, and subjected to flash chromatography (1-3% MeOH—CH2Cl2) to give 4-chloro-5-(ethyloxy)-7-(methyloxy)quinazoline (260 mg, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H), 7.03 (d, J=2.51 Hz, 1 H), 6.84 (d, J=2.26 Hz, 1 H), 4.22 (q, J=6.86 Hz, 2 H), 3.96 (s, 3 H), 1.47 (t, J=6.90 Hz, 3 H). MS (m/z) 239.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13](OCC)(=[O:19])[C:14](OCC)=[O:15]>>[NH:1]1[C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]3=[CH:10][C:11]=2[NH:12][C:14](=[O:15])[C:13]1=[O:19]
Reactant: Nc1cc2ccccc2cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc3ccccc3cc2[nH]c1=O
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 2,3-diaminonaphthalene (2.87 g, 18.14 mmol) and diethyl oxalate (30 mL, 223 mmol) was heated to reflux for 14 hours, cooled to RT and filtered. The residue was washed with EtOH and dried in vacuo to give the title compound as a brown solid (3.15 g, 82%); mp>350° C.; IR (KBr, cm−1) 3045, 2942, 2869,1716, 1642,1406, 877; 1H NMR (DMSO) δ 12.11 (s, 2H), 7.84-7.81 (m, 2H), 7.54 (s, 2H) 7.39 (dd, J=6.3, 3.0, 2H); LC/MS 92.5% (220 nm), m/z (M+H+) 213.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2C1O[C@H](CO)[C@@H](O)[C@H]1O)[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[CH2:1]([N:8]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccccc1)c1ncnc2c1ncn2C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Product: CC(C)N(Cc1ccccc1)c1ncnc2nc[nH]c12
Yield: 75 %

Procedure:
A solution of 3.5 g. (mmol) 6-[N-benzyl-N-(2-propyl)-amino]-9-ribofuranosylpurine and 50 ml. 2N hydrochloric acid is heated under reflux for 30 minutes. After cooling, it is washed with diethyl ether, the aqueous phase is adjusted to pH 7 with aqueous ammonia solution and the precipitate is recrystallized from aqueous propan-2-ol. There is obtained 1.8 g. of the title compound (75% of theory); m.p. 200°-202° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[CH3:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[CH:7]1[CH2:8][C:9](=[O:12])[CH2:10][CH2:11][N:6]1[C:4]2=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)N2C=CC(=O)CC2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(=O)N1CCC(=O)CC21
Temperature: 95 °C
Yield: 31.8 %

Procedure:
A mixture of 1-(2-bromo-5-methylbenzoyl)-2,3-dihydro-4-pyridinone (1.19 g, 4.03 mmol), tri-n-butyltin hydride (1.14 ml, 4.24 mmol) and azobis(isobutyronitrile) (AIBN, 66 mg, 10 mol %) in toluene (40 ml) was heated at 95° C. for 2 h, cooled, evaporated and purified by flash column chromatography on silica eluting with 30% ethyl acetate in hexane to yield the title compound as a pale yellow oil (276 mg), MS (+EI) m/z 215 [M+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[C:35]([O:34][C:32]([C:31](=[O:39])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and tert-butyl 2-chloro-2-oxoacetate (0.064 mL, 0.40 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 21 mmHg]. Yield 44 mg (66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:24]([NH2:31])[C@H:23]1[OH:32]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:31][C@@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][C@@H:23]2[OH:32])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.