Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O1CCOCC1>Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:8]3[C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=4[S:10][CH:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3csc4ccnc(N)c34)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1,1-dimethylethyl 5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (5.19 g, 14.12 mmol) was taken up in 4 M HCl in dioxane (100 ml, 400 mmol) as a slurry and left to stir at room temperature overnight. The reaction was then filtered and washed with dioxane to afford 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (3.44 g) as an off white solid. LC/MS (ES) m/z=268.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[C:29](=[O:46])[N:30]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]([CH3:37])=[N:32]3)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.31 g, 1.8 mmol) in DMF in a 40° C. oil bath (8 mL), was added 1,1′-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.62 g, 1.8 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as an off-white solid (580 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (98.5%); mp, 285° C. (decomposed); 1HNMR (DMSO-d6)2.14-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 3.54 (s, 2H, ArCH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.26-7.72 (m, 7H, Ar), 8.39 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.59, 41.49, 41.72, 56.48, 117.68, 124.72, 125.59, 128.13, 130.92, 131.08, 133.82, 135.32, 140.64, 148.44, 154.80, 160.90, 169.50, 169.88, 172.59. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl+0.15H2O+0.06 CH2Cl2: C, 60.12; H, 4.69; N, 12.16; Cl, 8.62. Found: C, 59.78; H, 4.60; N, 12.22; Cl, 9.00.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2
Reactant: CN1CCNCC1
Product: CN1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1

Procedure:
In the same manner as described in example 3, starting from 2,10dicloro-8-fluoro-10,11dihydro-dibenzo[b,f]thiepin and N-methylpiperazine, there is obtained 1-[2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl]-4-methyl-piperazine which melts at 118°-120°. After recrystallisation of this base from ether and reaction with maleic acid the correponding maleate is obtained which melts at 174°-175°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][O:5][CH2:4]1.O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]1(=[O:15])[N:10]([O:1][CH2:2][CH:3]2[CH2:8][O:7][CH2:6][O:5][CH2:4]2)[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1COCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1COCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of 5-hydroxymethyl-1,3-dioxane (3.90 g, 33 mmol), N-hydroxyphthalimide (6.46 g, 39.6 mmol) and triphenylphosphine (10.39 g, 39.6 mmol) in tetrahydrofuran (150 ml) was cooled to O° C. and stirred during the addition of diethyl azodicarboxylate (6.24 ml, 39.6 mmol). The solution was then stirred for 16 h at 25° C. and evaporated to dryness. The residue was triturated twice with ether, evaporated to dryness then chromatographed in chloroform/methanol (40:1) to give 5-phthalimidooxymethyl-1,3-dioxane (6.63 g, 76.3%) as a white solid; m.p. 98-106° C.: νmax (KBr) 1780, 1735, 1470, 1400, 1160 cm-1 ; δH (CDCl3) 2.20(1H, m, CH), 4.07(4H, m, OCH2CHCH2O), 4.37(2H, d, J6.88 Hz, CH2ON), 4.86(2H, m, OCH2O), 7.8I(4H, m, C6H4); Found: C,59.31; H, 5.03; N, 5.31%; C13H13NO5 requires: C, 59.31; H, 4.98; N, 5.32%; m/z 264(MH+, 100%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[CH2:7][C:6]2=[N:18]S(C(C)(C)C)=O>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][CH2:11][O:10][CH2:9]1)[CH2:7][C:6]2=[NH:18]
Reactant: CC(C)(C)S(=O)N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Product: N=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
HCl (4 M in 1,4-dioxane) (0.395 mL, 12.99 mmol) was added to a suspension of N-(6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-ylidene)-2-methylpropane-2-sulfinamide (Example 45 Step 1, 520 mg, 1.30 mmol) in anhydrous 1,4-dioxane (6 mL) and the resulting mixture was stirred under a nitrogen atmosphere at r.t. for 2 days. A precipitate was formed. The precipitate was filtered off and washed with Et2O. The solid was then dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic layer was collected and concentrated. The title compound was used directly in the next step without any further purl fi cation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11]Br.[C-:14]#[N:15].[Na+]>CN(C=O)C.CCOCC.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(Cl)c1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cccc(Cl)c1CC#N
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a solution of crude 2-bromomethyl-3-chlorobenzoic acid methyl ester (30.4 mmol) in DMF (60 mL), was added finely powdered sodium cyanide (2.22 g, 45 mmol). The reaction mixture turned brown rapidly, and became warm. The dark suspension was then immersed in an oil bath held at 55° C. The reaction mixture was allowed to stir at 55° C. for 1.5 hours, at which time heating was discontinued, and the reaction was allowed to cool to ambient temperature. After stirring at ambient temperature for 16 hours, the reaction was diluted with ether (300 mL) and water (200 mL). The layers were separated, the aqueous was extracted with ether (3×75 mL), and the combined organic extracts were washed with water (3×50 mL). The organic layer was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude oil was purified by flash chromatography eluting with a gradient from 0% to 16% ethyl acetate/hexane to afford 3-chloro-2-cyanomethylbenzoic acid methyl ester (3.9 g, 65% yield over two steps) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.96 (1H, dd, J=8.1 Hz, 1.3 Hz), 7.65 (1H, dd, J=8.1, 1.3), 7.4 (1H, t, J=7.9Hz), 4.35 (2H, s), 3.97 (3H, s) ppm.
Reaction SMILES: [I-].[CH3:2][N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH2:4]1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH2:4]1
Reactant: CN1C=CC=C(CCCN2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: CO
Solvent: O
Product: CN1CCCC(CCCN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a cooled (−78° C.) suspension of the product of step b (1.49 g, 3.65 mmol) in methanol (36 ml) was added portionwise sodium borohydride (270 mg, 7.30 mmol) and the resultant suspension stirred at this temperature for 20 minutes. The suspension was allowed to warm to 0° C. and the reaction stirred for a further 30 minutes. The suspension was treated with aqueous 2M hydrochloric acid (3.6 ml) and the stirring was continued for a further 1 h. The reaction mixture was treated with sufficient aqueous 2M sodium hydroxide to pH 11 and water (100 ml) was added. The aqueous phase was extracted thrice with DCM (100 ml) and the combined organic extracts were dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue was dissolved in methanol (10 ml) and treated with palladium on charcoal (150 mg). The resultant suspension was stirred under a hydrogen atmosphere (via balloon) for 16 h. The suspension was filtered through a pad of celite and the filter-cake was washed with methanol (100 ml). The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography (90:10:1 DCM:methanol:ammonia) to obtain the title compound (437 mg, 42%). 1H NMR 7.87-7.82 (2H, m), 7.74-7.69 (2H, m), 3.72-3.65 (2H, m), 2.89-2.82 (2H, m), 2.28 (3H, s), 1.89-0.84 (1H, m).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9].C(NCC)C>C(Cl)Cl.C(#N)C>[NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Solvent: CCNCC
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C

Procedure:
Fmoc-Lys(Mtr) 1 (5.25 g, 8.19 mmol) in 1:1 methylene chloride/acetonitrile (80 mL) at rt was treated with diethylamine (80 mL). After 1.5 h the solvents were evaporated. The residue was flushed with acetonitrile (2×50 mL) at 60° C., and then triturated with ether (80 mL). The resulting solid was collected by filtration, washed with ether, and then dissolved as far as possible in 1:1 methylene chloride/methanol. Some solid byproduct was removed by filtration and the filtrate was concentrated invacuo. The resulting light tan solid was dried in vacuo for 4 h (3.2221 g, 94%). 1H-NMR (DMSO-d6) δ 1.34, 1.57 and 1.72 (m, 6H), 2.05 (m, 2H), 3.38 (m, 1H), 3.68 (s, 3H), 3.71 (d, 2H), 7.03-7.40 (m, 12H). MS (FAB) 419.2 (MH)+, 441.4 (M+Na)+, 457.4 (M+K)+. MS (FAB) 419.2 (MH)+, 441.4 (M+Na)+, 457.4 (M+K)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)(C)(C)C.[F:25][C:26]([F:38])([F:37])[C:27]1[N:36]=[C:30]2[C:31](=S)[NH:32][CH2:33][CH2:34][N:29]2[N:28]=1>COCCO>[F:23][C:16]1[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=1[CH2:14][C@@H:8]([NH2:7])[CH2:9][C:10]1[N:32]2[C:31]([C:30]3[N:29]([N:28]=[C:27]([C:26]([F:38])([F:37])[F:25])[N:36]=3)[CH2:34][CH2:33]2)=[N:13][N:12]=1
Reactant: FC(F)(F)c1nc2n(n1)CCNC2=S
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: COCCO
Product: N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCn1nc(C(F)(F)F)nc1-2

Procedure:
A mixture of 208 mg (0.6 mmol) of of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 100 mg (0.45 mmol) of 2-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrazine-8(5H)-thione (Intermediate 7), and 5 mL of 2-methoxyethanol was stirred at reflux for 18 h, resulting primarily in ring closure of the initial adduct as well as loss of the Boc group. The cooled solution was purified by preparative HPLC (C18 reverse phase column, 30-75% acetonitrile in water containing 0.05% trifluoroacetic acid) to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>CCOCC>[C:4]1([C:1]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNC1
Reactant: CC(=O)c1ccccc1
Solvent: CCOCC
Product: C=C(c1ccccc1)N1CCCC1
Temperature: 500 °C

Procedure:
100 g of molecular sieve are heated at 500° C. for 8 hours and then added to a mixture of 20 mmol of acetophenone and 22 mmol of pyrrolidine in 200 ml of anhydrous ether. The reaction mixture is stirred at ambient temperature until, in the infra-red, no more free ketone (C═O 1689 cm−1) is detected in the supernatant and the absorption for the enamine (C═C—N 1600 cm−1) is at a maximum. The mixture is then filtered and the molecular sieve is washed with ether. The solvent is evaporated off under reduced pressure and the crude residue is purified by distillation under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][NH2:29]>O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:29][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNCc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
5-bromo-3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (100 mg, 0.2433 mmol) and sodium carbonate (77.36 mg, 0.7299 mmol) were suspended in and treated with methanamine (182.5 μL of 2 M, 0.3650 mmol). The reaction was heated at 60° C. for 10 minutes. The remaining excess of methanamine (425.8 μL of 2 M, 0.8515 mmol) was then added and the reaction heated at 60° C. for a further 10 minutes. The reaction was cooled, diluted with water and extracted into dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 5-bromo-3-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (75 mg, 0.2076 mmol, 85.34%) as a yellow solid. LC/MS m/z 362.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>C(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C@@H:25]([OH:27])[CH2:26][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:20]=[CH:19][CH:18]=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=3)[CH2:3]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1cccc(C2CCCC(N)C2)c1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: CCOC(=O)COc1cccc(C2CCCC(NC[C@H](O)c3cccc(Cl)c3)C2)c1
Yield: 61.8 %

Procedure:
Ethyl 3-(3-aminocyclohexyl)phenoxyacetate (8.47 g) was dissolved in ethanol (50 ml), and (R)-3-chlorostyrene oxide (4.72 g) was added prior to heating to reflux for 7.5 hours. After allowing the mixture to cool, the solvent was concentrated under reduced pressure to obtain an oily substance which was then separated and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5), to give 8.15 g of (1R)-1-(3-chlorophenyl)-2-[3-(3-ethoxycarbonylmethoxyphenyl) cyclohexylamino]ethanol (trans-H) (compound of Example 11) as an oily substance (61.8% yield).
Reaction SMILES: C[O:2][C:3](=[O:72])[C@@H:4]([NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:64](=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C@H:37]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C1COCC1.C(O)C>[C:64]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[NH:57][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C@H:37]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:38]([OH:40])=[O:39])=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)=[CH:8][CH:7]=1)[C:3]([OH:72])=[O:2])(=[O:71])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)OC)cc3)cc2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1N[C@@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](Nc4ccccc4C(=O)c4ccccc4)C(=O)O)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)(E)(S)(S) 2-(2-benzoyl-phenylamino)-3-(4-{5-[4-(5-{4-[2-(2-benzoyl-phenylamino)-2-methoxycarbonyl-ethyl]-phenoxy}-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-ynyloxy}-phenyl)-propionic acid methyl ester (example 9) (370 mg 0.39 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from ethyl acetate and petroleum ether to give 200 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]#[C: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[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][CH:9]=[CH: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[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamic acid tert-butyl ester is prepared by adding (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (3.00 g, 5.63 mmol) to a mixture of Red-Al (5 ml of a 65% wt solution in toluene) in THF (50 ml) at 0° C. under N2. After stirring for 3 h at 0° C., the reaction mixture is quenched by the addition of 10 ml of 10% K2CO3 solution followed by water. The reaction mixture is extracted with ethyl acetate. The organic extracts are dried (Na2SO4), concentrated, and purified by column chromatography (EtOAc:Hex 1:1) to provide 2.01 g (67%) clean desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1C(F)(F)F

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-bromo-2-(trifluoromethyl)benzenesulfonyl chloride and benzene.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>O>[C:1]1([C:7]2[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Oc1ccccc1-c1ccccc1
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
To a 100 ml. beaker, 25 g. of the starting phenylphenol mixture used in Example 1, above, and water containing 1.0 g. of sodium hydroxide were added. The mixture was heated to 95° C. and stirred for 10 minutes after reaching this temperature. This gave a mole ratio of caustic to m-phenylphenol of about 5.55 to 1. Water was added to maintain volume. The solid was collected on a filter. The cake was treated with small amounts of hydrochloric acid and dried. The resulting p-phenylphenol was analyzed and shown to have 1.2% of m-phenylphenol present therein.
Reaction SMILES: COC(=O)[C@@H:4]1CCC[N:5]1[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(O)(=O)CCCCCCCCCCC/C=C\CCCCCCCC.CN>>[CH3:4][NH:5][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CN
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)NC
Reaction time: 0.5 h
Yield: 51 %

Procedure:
In a manner similar to (i), erucic acid (3.39 g) was converted to its acid chloride, to which was added a 40% aqueous solution of methylamine. The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was subjected to extraction with isopropyl ether. The extract was dried and concentrated. The concentrate was recrystallized from hexane to afford pale orange crystals [1.80 g (yield 51%)], m.p. 48 to 49° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccnc2cccnc12
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccnc3cccnc23)cc1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A mixture comprising 150 mg (0.911 mmole) of 4-chloro-1,5-naphthyridine and 1.00 g of 4-fluorophenol was heated at 160° C. After one hour, the mixture was cooled and dissolved in ethyl acetate and 2N sodium hydroxide. The organic layer was washed twice with base to remove excess 4-fluorophenol. The organic layer was then dried with magnesium sulfate and concentrated, producing an oil that slowly crystallized. This product was recrystallized in heptane, giving 103 mg of the title product. MP 122°-124° C. Yield 47%.