Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=1)([O-])=O.O>C(O)(=O)C.[Zn]>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Oc2ccccc2)cn1
Temperature: 105 °C
Yield: 90 %

Procedure:
8.2 2-Nitro-5-phenoxy-pyridine (11.3 mmol) is dissolved in acetic acid (30 ml) at 35° C. After addition of water (30 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 105° C. for 2.5 h. The reaction suspension is cooled to RT and filtrated. The filtrate is poured into 3.5% NaOH (700 ml) and extracted with dichloromethane. The combined organic phases are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Phenoxy-pyridin-2-ylamine is obtained as a pink powder in a yield of 90%; HPLC (method C): 1.32 min, LC-MS (method A): 0.531 min, 187.15 (M+H+).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)CCC>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:28][CH2:27][CH2:25][OH:26])[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1OC
Reactant: NCCO
Agent: Cl
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cc1OC
Temperature: 110 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine hydrochloride (63 mg; 0.172 mmol) and ethanolamine (32 μL; 0.53 mmol) in n-butanol (2 mL) was heated at 110° C. for 24 h then concd in vacuo. The material was partitioned between DCM (5 mL) and satd NaHCO3 (3 mL). The organic layer was dried (MgSO4), filtered through silica and washed with 100:10:1 CHCl3:MeOH:concd NH4OH, concd then purified by pTLC (EM-13793; 100:10:1 CHCl3:MeOH:concd NH4OH) yielding a pale yellow glass (52 mg; 85%). 1H NMR (CDCl3) δ 7.44-7.34 (m, 2H), 6.88 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.75-6.67 (m, 3H), 5.42 (t(br), 1H), 3.91 (s, 3H), 3.91 (m, 2H), 3.79 (s, 3H), 3.68 (m, 2H), 3.50 (s, 3H); LC-MS (ESI+; 355 ([M+H]+).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:15])([F:14])[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:12]([C:10]1[N:11]=[C:7]([C:6]([F:5])([F:14])[F:15])[S:8][CH:9]=1)[OH:13])#[CH:2]
Reactant: C#C[Mg]Br
Reactant: O=Cc1csc(C(F)(F)F)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1csc(C(F)(F)F)n1

Procedure:
11 cm3 of a molar solution of ethynyl magnesium bromide is added to a solution of tetrahydrofuran containing 2 g of 2-(trifluoromethyl) 4-thiazolecarboxaldehyde. The reaction mixture is maintained under agitation for 30 minutes at about 20° to 25° C. It is poured into a solution of ammonium chloride, followed by extraction with methylene chloride, drying, filtering and bringing to dryness. 2.1 g of desired product is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCSc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Hydroxy-propylsulfanyl)-phenol (CAB02029, 3.686 g, 20 mmol) was dissolved in ethanol (50 mL) and potassium tert-Butoxide (2.80 g, 25 mmol) and benzyl bromide (3.0 mL, ca. 25 mmol) were added. The mixture was stirred overnight at room temperature, the precipitated potassium bromide was filtered off and the filtrate was concentrated under reduced pressure. The resulting yellow solid was dissolved in ethyl acetate (100 mL), the solution was washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (ca. 10 mL) and the product was precipitated by addition of hexane (ca. 200 mL). The crystalline product was collected and dried under high vacuum. Yield: 4.481 g (82%) colourless, small plates. 1H-NMR (400 MHz, CDCl3) δ=1.45 (br s, 1H, —OH), 1.82-1.87 (m, 2H), 2.84 (t, J=7.4 Hz, 2H), 3.74-3.78 (m, 2H), 5.05 (s, 2H, —OCH2Ph), 6.90-6.93 (m, 2H), 7.31-7.44 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([OH:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.C([O-])(O)=O.[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O>[C:17]([O:11][C:4]1[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]2=[C:2]([CH3:1])[N:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(O)cc2ccsc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Oc1cc2ccsc2c(C)n1
Temperature: 0 °C
Yield: 62 %

Procedure:
A solution of 7-methylthieno[2,3-c]pyridin-5-ol (5.0 g, 30.3 mmol) and concentrated sulfuric acid (3 drops) in acetic anhydride (50 ml) was stirred at room temperature for 16 hours. The mixture was poured into ice water (300 ml), neutralized with NaHCO3, and was extracted with CH2Cl2. The organic layer was washed with a saturated solution of NaHCO3, dried over MgSO4, treated with activated charcoal and evaporated in vacuo to give the product (3.9 g, 62% yield) as an amber oil; IR (neat) 3090, 1770 and 1585 cm-1 ; mass spectrum m/z 207 (M+); 1H NMR (CDCl3) δ2.35 (s, 3H, COCH3), 2.75 (s, 3H, CH3), 7.28 (d superimposed on s, J=5 Hz, 2H, thiophene-H, Ar-H), 7.67 (d, J=5 Hz, 1H, thiophene-H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34](=[O:35])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:40])[CH:37]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (130 mg, 0.45 mmol, 1.91 equiv), EDC.HCl (67 mg, 0.35 mmol, 1.50 equiv), 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 3×10 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 108.6 mg (66%) of a white solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.66-8.64(d, J=8.8 Hz, 1H), 8.39(s, 1H), 8.16 (s, 3H), 8.07-8.05(d, J=7.6 Hz, 1H), 7.99(s, 1H), 7.79(s, 1H), 7.16-7.68 (m, 3H), 7.61(s, 1H), 7.07(s, 1H), 4.11-4.10(d, J=3.2 Hz, 2H), 3.98 (s, 3H), 3.80-3.77(m, 4H), 3.59-3.54 (m, 6H), 3.14(m, 4H), 1.99-1.79(m, 6H). MS (ES, m/z): 704 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH3:33])[C:31]5[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=5[N:29]=4)[CH:23]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:38]CCl>Cl.CCOCC>[ClH:38].[CH3:33][N:32]1[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=[C:28]1[C:24]1[CH:23]=[C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17]2)[CH:27]=[CH:26][CH:25]=1
Reactant: ClCCl
Reactant: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)nc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCNCC4)C3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Method A—Step b To a mixture of 4-{(S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 0.08 mmol) in dichloromethane (0.5 mL), 2M HCl in Et2O (2 mL) was added and the resulting mixture was stirred overnight at room temperature. Solvent was removed to get 0.04 g of the title compound as hydrochloride salt with quantitative yield.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C)=[C:9]([CH3:25])[C:8]([OH:26])=[C:7]([O:27][CH3:28])[C:6]=1[O:29][CH3:30])(=O)C.Cl.[Cl:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:32].[CH3:30][O:29][C:6]1[C:7]([O:27][CH3:28])=[C:8]([O:26][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:9]([CH3:25])=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:5]=1[OH:4]
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)c(CCCCCCCCCCO)c(C)c(OCc2ccccn2)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of 1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene (2.1 g) obtained in Example A-5, 2-chloromethylpyridine hydrochloride (2 g), potassium carbonate (5 g) and dimethylformamide (15 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was dissolved in methanol (20 ml). Aqueous 1N sodium hydroxide solution (20 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate, and the eluate was concentrated. The residue was dissolved by adding ethanol (30 ml), and conc. hydrochloric acid (0.7 ml) was added. The crystals obtained after concentration under reduced pressure were separated by filtration using ether to obtain the desired compound (1.7 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:26].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A reaction mixture comprising of 3,5-dichlorobenzyl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate (947 mg, 2.269 mmol) and 4M HCl in dioxane (2.84 mL, 11.35 mmol) in DCM (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as the hydrochloride salt;
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[NH:22]([CH3:24])[CH3:23]>C(Cl)Cl.CCO>[CH3:23][N:22]([CH3:24])[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CNC
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(c1cccc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (40 mg, 97.3 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with Me2NH (174 μL of a 5.6 M solution in EtOH, 973 μmol) at rt for 1 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 30-60% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (10.6 mg, 11% over two steps). MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)OCc1ccccc1
Reactant: CN(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.2 %

Procedure:
(S)-2-(Benzyloxycarbonylamino)-7-hydroxytetralin (13.4 g) was dissolved in 120 ml of N,N-dimethylformamide, 8.27 g of 2-bromo-N,N-dimethylacetamide and 22.0 g of cesium carbonate were added to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice-water, the mixture was extracted with ethyl acetate, and the extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was crystallized by adding diethyl ether to give 14.0 g of (S)-2-[2-(benzyloxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide having a melting point of 117 to 118° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:29](=[O:30])[C:28]#[C:27][C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=2[Cl:16])=[CH:11][CH:12]=1)[CH3:15]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 69 mg (0.33 mmol) of 4-(2-diethylaminoethoxy)phenylamine and 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 70 mg (53% of theory); melting point: 194° C.-197° C.; C22H22ClF3N2O2 (M=438.88); calc.: molecular ion peak (M+H)+: 439/441; found: molecular ion peak (M+H)+: 439/441; Rf value: 0.35 (silica gel, dichloromethane/methanol=(9:1)).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[C:35](OC)=[O:36])[N:28]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[C:35]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:36])[N:28]=3)[NH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: COC(=O)C1CCCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)C1CCCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (586 mg, 5.2 mmol) in dry THF (20 mL) was added 2M solution of isopropylmagnesium chloride in THF (2.6 mL, 5.2 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxylate (500 mg, 1.31 mmol) in THF (4 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 3 h. The reaction was quenched with saturated ammonium chloride solution (40 mL). The product was extracted with EtOAc (2×75 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide (12 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.58-0.68 (m, 2H), 0.82-0.97 (m, 2H), 1.60-1.90 (m, 6H), 2.10-2.24 (m, 3H), 2.30-2.41 (m, 1H), 2.77-2.81 (m, 2H), 2.81-2.91 (m, 2H), 4.46 (d, 1H), 5.39 (s, 1H), 6.06 (s, 1H), 7.00 (dd, 1H), 8.02-8.12 (m, 1H), 8.27 (s, 1H). Separation by chiral HPLC provided enantiomers 9a and 9b.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2Cl>CN(C=O)C>[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc2ncnc(Oc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A suspension of NaH (washed free of mineral oil) in DMF (40 mL) was cooled to 0° C. and a solution of phenol (5.65 g, 60 mmol) in DMF (20 mL) was added dropwise. Upon completion of addition, 6-iodo-4-chloroquinazoline (14.6 g, 50.3 mmol) was added as a solid in small portions. The cooling bath was moved and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water (200 mL), diluted with EtOAc (300 mL) and transferred to a separatory funnel. The organic layer was washed with dilute aqueous NaOH, water and brine and dried over Na2SO4. Filtration of the solids and removal of the solvent provided quinazoline 13 (17.2 g, 98%) as a yellow solid. 1H NMR (400 MHz; CDCl3): δ 8.74 (d, 1H), 8.14 (s, 1H), 8.12 (dd, 1H), 7.71 (d, 1H), 7.49 (dd, 2H), 7.32 (t, 1H), 7.22 (m, 2H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([NH:7][CH2:8][CH2:9][O:10][CH3:11])[CH3:6]>CCOCC>[CH3:11][O:10][CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCNCCOC
Solvent: CCOCC
Product: CCN(CCOC)C(=O)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 89.1 g. phosgene in 500 ml. dry ether at -20°C. was added a solution of 30.9 g. N-ethyl-N-2-methoxyethylamine in 50 ml. dry ether, whilst the temperature of the reaction mixture was maintained at -20°C. The stirred mixture was then allowed to warm to room temperature during 1 hour. The reaction mixture was filtered and the filtrate evaporated in vacuo below 25°C. to remove the solvent and give the product, N-(2-methoxyethyl)-N-ethylcarbamoyl chloride as a pale yellow liquid.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[Cl:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=3[Cl:46])=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (7.5 mL, 22.6 mmol) was added to a THF (40 mL) and MeOH (20 mL) solution of ethyl 3-(5-(5-chloro-2-(((2′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (6.6 g, 11.3 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][C:21]([O:27][CH3:28])=[CH:22][CH:23]=2)[N:18]=1>O>[CH3:28][O:27][C:21]1[N:20]=[C:19]2[C:24]([CH:25]=[CH:26][C:17]([NH:16][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)Nc1cccc(C(=O)O)c1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Product: CCOC(=O)Nc1cccc(C(=O)Nc2ccc3ccc(OC)nc3n2)c1
Yield: 58.7 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 3-ethoxycarbonylaminobenzoic acid (10 g), N,N'-carbonyldiimidazole (7.6 g) and 2-amino-7-methoxy-1,8-naphthyridine (5.95 g). The reaction mixture is then poured into water (1000 cc) and the precipitate formed is separated by filtration, washed with water (10 cc) and dried in the air. On recrystallization in ethyl acetate (100 cc) of the product thereby obtained, N-(7-methoxy-1,8-naphthyridin-2-yl)-3-ethoxycarbonylaminobenzamide (7.3 g), m.p. 120° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Temperature: 45 °C
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-benzyloxy-1-methyl-1H-indole-2-carboxylate (3.09 g) in THF (200 mL) was added LiOH.H2O (1.26 g) in water (200 mL) and the resulting two phase solution was heated at 45° C. under nitrogen overnight. The cooled reaction mixture was evaporated to remove THF and the remaining aqueous solution was acidified with NaHSO4 to precipitate the title compound, which was collected, washed with water, and dried to give 2.87 g of the title compound. M.P. 216.6–216.8° C.
Reaction SMILES: [C:1]([C:4]1([OH:26])[CH2:21][CH2:20][C:19]2[C:6](=[C:7]([OH:25])[C:8]3[C:9](=[O:24])[C:10]4[C:15]([C:16](=[O:22])[C:17]=3[CH:18]=2)=[C:14]([OH:23])[CH:13]=[CH:12][CH:11]=4)[CH2:5]1)(=[O:3])[CH3:2].[CH2:27](O)[CH2:28][OH:29]>C1C=CC=CC=1>[CH2:27]1[CH2:28][O:29][C:1]([C:4]2([OH:26])[CH2:21][CH2:20][C:19]3[C:6](=[C:7]([OH:25])[C:8]4[C:9](=[O:24])[C:10]5[C:15]([C:16](=[O:22])[C:17]=4[CH:18]=3)=[C:14]([OH:23])[CH:13]=[CH:12][CH:11]=5)[CH2:5]2)([CH3:2])[O:3]1
Reactant: CC(=O)C1(O)CCc2cc3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O
Reactant: OCCO
Solvent: c1ccccc1
Product: CC1(C2(O)CCc3cc4c(c(O)c3C2)C(=O)c2cccc(O)c2C4=O)OCCO1

Procedure:
A solution of (±)-2-acetyl-2,7,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (740 mg; 2.1 mmol) and ethylene glycol (280 mg; 4.4 mmol) in 400 ml of benzene, in the presence of a catalytic quantity of paratoluenesulfonic acid, is heated under reflux for 12 hours in a 500 ml round-bottomed flask. The flask is equipped with a "Dean Stark" apparatus (making it possible to remove the water formed as an azeotrope with benzene).