Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 26 %

Procedure:
(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (26% yield). HPLC: 97%, RT=3.608 min. MS: m/z=482 [M+H]+, RT=3.57 min. 1H-NMR (DMSO-d6), δ 10.33 (s, 1H), 9.66 (s, 1H), 8.01 (s, 1H), 7.66-7.64 (m, 2H), 7.38 (t, 1H), 7.32 (t, 2H), 7.11-6.92 (m, 8H), 6.68 (m, 1H), 6.41 (m, 3H), 3.88 (m, 2H), 2.73 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[CH3:26][N:27]1CCOCC1.Cl.CN.Cl>C1COCC1>[CH3:26][NH:27][C:17](=[O:19])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
N-Benzyloxycarbonyl tert-leucine (24.7 mmol, 6.56 g) was taken up in dry THF (50 ml) and the solution cooled to -40° C. under a nitrogen atmosphere. Ethyl chloroformate (26 mmol, 2.84 g) was added and the solution left to stir for 10 min. N-methylmorpholine (52 mmol, 5.24 g) was added and the solution stirred for 50 min between -20° C. and -40° C. before adding neat methylamine hydrochloride (24.7 mmol, 1.67 g). The solution was allowed to warm to RT and stirred at this temperature for 18 hr. The solution was poured into 10% HCl (50 ml), extracted with EtOAc (50 ml×3), the combined organic layer washed with saturated sodium bicarbonate solution (1×55 ml), then brine (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound (5.72 g) as an off-white solid. δH (CDCl3) 1.0 (9H, s), 2.75 (3H, d), 3.6 (1H, d), 5.0-5.1 (2H, m), 5.65 (1H, d), 6.25 (1H, s), 7.25-7.4 (5H, m) and 8.0 (1H, s).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]=[C:20]=[S:21]>>[CH3:18][NH:19][C:20]([NH:1][CH:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:21]
Reactant: NC1CCCc2ccc(-c3ccccc3)nc21
Reactant: CN=C=S
Product: CNC(=S)NC1CCCc2ccc(-c3ccccc3)nc21

Procedure:
The 8-amino-compound of Example 23 may be treated with methylisothiocyanate to give the title compound following the procedure of Example 4.
Reaction SMILES: [C:1]1([S:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(/C=C/c1ccc2[nH]ccc2c1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(CCc1ccc2[nH]ccc2c1)c1ccccc1
Yield: 85 %

Procedure:
A suspension of (E)-5-(2-(phenylsulfonyl)vinyl)-1H-indole (5.0 g) in 50 ml methanol, 10 ml THF and 10% Pd/C (1.0 g) was subject to hydrogenation at 45-50 psi. Upon completion of the reaction the catalyst was filtered off and the solvent removed under vacuum to provide the title compound in about 85-90% yield as an off-white solid. 1H NMR CDCl3 δ=8.15 (bs, NH), 7.93-8.00 (m, 2H), 7.53-7.70 (m, 3H), 7.38 (s, 1H), 7.30 (d, 1H), 7.20 (dd, 1H), 6.93 (dd, 1H), 6.42-6.48 (m, 1H), 3.37-3.46 (m, 2H), 2.99-3.17 (m, 2H). ESI Mass (M+23) 308.4
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2OCC[O:14]2)=[O:9])[NH:5][C:6]=1[Br:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]=[O:14])=[O:9])[NH:5][C:6]=1[Br:7]
Reactant: O=C(NCCC1OCCO1)c1cc(Br)c(Br)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=CCCNC(=O)c1cc(Br)c(Br)[nH]1
Yield: 90.8 %

Procedure:
A mixture of 11 (5.0 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.84 mmol) in 80 mL of acetone/water (1:1) was refluxed for 12 h. After cooling, the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was recrystallized from acetone/CH2Cl2 to afford 12 (4.0 g, 91%) as a colorless solid: mp 160-163° C.; 1H NMR (CD3COCD3) d 2.73 (td, 2H, J=6.5, 1.5), 3.63 (q, 2H, J=6.5 ), 6.85 (d, 1H, J=2.9), 7.63 (br, 1H), 9.75 (t, 1H, J=1.5), 11.73 (br, 1H); 13C NMR (CD3COCD3) d 33.9 (e), 44.3 (e), 99.5 (e), 105.6 (e), 113.3 (o), 128.8 (e), 160.3 (e), 201.6 (o); IR (nujol) 3212, 1715, 1610, 1561 cm−1; MS, m/z (relative intensity) 327 (M++5, 50), 325 (M++3, 100), 323 (M++1, 50), 247 (25), 226 (22), 171 (20), 127 (19); Anal. Calcd for C8H8N2O2Br2: C, 29.66; H, 2.49; N, 8.65; Found: C, 29.49; H, 2.57; N, 8.53.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.CN(C)C=O.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[N:32]([CH2:33][CH2:34][N:3]3[C:2]([CH3:1])=[N:6][N:5]=[N:4]3)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnnn1CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Yield: 34.8 %

Procedure:
Treat a stirred solution of 5-methyltetrazole (0.38 g, 4.52 mmol, obtained from TCI US) and dimethylformamide (7 mL) at 0° C. portionwise with sodium hydride (0.19 g, 4.75 mmol, 60% dispersion in oil). Allow to warm to room temperature over one hour and add a solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (0.1.33 g, 3.03 mmol, Preparation 28) and dimethylformamide (7 mL). Heat at 100° C. for 6 hours. Cool, add ethyl acetate (50 mL) and wash with saturated NaHCO3 (3×25 mL) and brine (3×50 mL). Dry (MgSO4) the organic phase, filter and concentrate in vacuo. Purify the residue by chromatography (silica gel, 3.5×50 cm) eluting with ethyl acetate:hexane (1:1) to afford 4-{1-[2-(5-methyl-tetrazol-1-yl}-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.45 g), Rf=0.21 (silica gel, methanol:dichloromethane, 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[S:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=O)C1CCNCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=S)C1CCNCC1

Procedure:
N-Ethoxycarbonylpiperidine-4-carboxamide (6 g 30 mmol) in toluene (300 ml) is treated with Lawesson's reagent (6.1 g 15 mmol) at room temperature for 18 h. The reaction mixture is evaporated and purified by SiO2 chromatography (acetone/cyclohexane 20/80) to yield the title compound, which is recrystallised from hexanes (3.6 g 52.5%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1
Yield: 79 %

Procedure:
Method E. Reaction of oxalyl chloride (195 λL, 2.2 mmol) and benzoic acid 4 (415 mg, 1.1 mmol) and subsequent coupling to 3-pyridinylmethylamine (125 λL, 1.2 mmol) gave benzamide 9 (406 mg, 79%) as a white powder: mp (EtOAc) 190-191° C.; 1H NMR δ 9.20 (t, J=5.8 Hz, 1 H, CONH), 8.57 (d, J=1.7 Hz, 1 H, H-2′), 8.47 (dd, J=4.8, 1.5 Hz, 1 H, H-6′), 8.00 (d, J=8.5 Hz, 2 H, H-2, H-6), 7.90 (d, J=8.4 Hz, 2 H, H-3, H-5), 7.74 (dt, J=7.8, 1.8 Hz, 1 H, H-4′), 7.67 (d, J=8.2Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.2Hz, 2 H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8Hz, 1 H, H-5′), 4.63 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 158.0, 149.9, 148.9, 148.1, 144.5, 135.6, 135.4, 135.2, 134.9, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 123.5, 53.0, 40.6, 21.0, 9.7; MS m/z 462.7 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.79; H, 5.03; N, 9.15%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][C@@H:27]3[O:41][C:31]4=[C:32]5[C:37](=[CH:38][CH:39]=[C:30]4[O:29][CH2:28]3)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]5)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: COc1ccc(N2CCN(C[C@H]3COc4ccc5nc(C)ccc5c4O3)CC2)cc1
Yield: 83.7 %

Procedure:
This compound was prepared as described for Example 5, using 4-methoxyphenyl piperazine (880 mg, 4.58 mmol) and 742 mg (1.65 mmol) of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate, to afford 560 mg (84%) of the title compound as a white solid: mp 164–165° C.; MS (ESI) m/z406 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:11]Br>CCOCC.C(Cl)(Cl)Cl>[Br:11][CH:2]([F:1])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CF)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccccc1)C(F)Br

Procedure:
To a solution of 2.76 g of 2-fluoroacetophenone in 50 ml of ether is added dropwise over 30 minutes a solution of 3.2 g of bromine in 10 ml of chloroform. Evaporation of the reaction mixture under reduced pressure affords α-bromo-2-fluoroacetophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:45])=[O:44])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NS(=O)(=O)c4ccccc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (254 mg) synthesized in Example A110(5) in N,N-dimethylacetamide was added benzenesulfonyl chloride (99 μL), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (312 mg, 96%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([Br:13])=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[Br:11])[C:5]([NH2:7])=[O:6].[Na].Br[CH2:16][C:17]([O:19][CH2:20]C)=[O:18]>CO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[C:4]([C:5](=[O:6])[NH2:7])[C:3]=1[Br:13]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(Br)cc(Br)c(O)c1Br
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1c(Br)cc(Br)c(C(N)=O)c1Br
Yield: 87.8 %

Procedure:
35.5 g (95 mmol) of 3-hydroxy-2,4,6-tribromobenzamide is suspended in 150 ml of methanol and dissolved by adding 2.18 g (95 mmol) of sodium. The mixture is combined with 17.5 g (104 mmol) of ethyl bromoacetate and maintained under reflux for three hours. After several hours of agitation, the crystallized product is vacuum-filtered, washed with a small amount of ice-cold methanol, and dried at 60° C., thus obtaining 37.2 g (88% of theory) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid methyl ester, mp 231°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH2:16].[OH-].[Na+:18]>O1CCCC1>[OH2:13].[OH2:16].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:18]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.49 g (content: 86%, net quantity: 9.02 g (47.3 mmol)) of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid and 30 ml of water. To this was added 47.3 ml (47.3 mmol) of a 1 mol/L sodium hydroxide aqueous solution. After completion of the reaction, the solution was condensed to dryness to obtain a solid to which 30 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes, then, the deposited crystal was isolated by filtration, and dried to obtain 11.28 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate di-hydrate as a yellow solid. Yield: 90%
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:21]1([C:27]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:28]2[C:32]([C:33]3[C:38]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=4)=[CH:37][CH:36]=[C:35]([F:47])[CH:34]=3)=[N:31][N:30]=[N:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([C:5]1[N:14]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([C:38]3[CH:37]=[CH:36][C:35]([F:47])=[CH:34][C:33]=3[C:32]3[N:28]([C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:29]=[N:30][N:31]=3)=[CH:44][CH:43]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]([CH3:17])[CH3:18])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C(C)C)ccc2[nH]1
Reactant: Fc1ccc(-c2ccc(CBr)cc2)c(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccc(F)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2-butyl-6-isopropylquinazolinone (55.6 mg; 0.228 mmol) (Example 8) in dry DMF (1.5 mL) was added NaH, 80% oil dispersion, (11.8 mg; 1.5 eq). The reaction mixture was allowed to stir for 30 min. under N2. To this was added a solution of N-triphenylmethyl-5-(4-fluoro-4'-bromomethyl-biphen-2-yl)tetrazole (crude) in dry DMF (1.5 mL). The reaction was stirred under N2 for 3 hrs. then quenched with saturated NH4Cl solution. The solvent was removed at high vacuum, replaced by EtOAc, and the insoluable salts filtered off. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc (35:1) to afford 94.5 mg (56%) of the titled compound. Characteristic peaks 1H-NMR (300 MHz, CDCl3) δ 0.87 (t, 3H), 1.30 (d, 6H), 1.68 (m, 2H), 2.63 (t, 2H), 3.05 (q, 1H), 5.28 (s, 2H), 8.13 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].[C:36]([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:36])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:14]([C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)c1cc(CO)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 80 %

Procedure:
To a cold (0° C.) solution of 2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-hydroxymethyl-benzoic acid methyl ester (0.290 g, 0.65 mmol) in THF (3 mL) was added a slurry of NaH (95% dry, 0.105 g, 4.38 mmol) in THF (10 mL) followed by neat Mel (0.40 mL, 6.43 mmol). The resultant mixture was stirred for 3 hours and treated with saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) gave COMPOUND 54 (239 mg, 80%) as a white solid. 1H NMR (CDCl3) δ 1.63-1.69 (m, 3H), 2.04-2.08 (m, 1H), 2.30-2.48 (m, 8H), 3.24 (s, 3H), 3.80 (s, 3H), 3.95 (s, 2H), 4.13 (d, 2H, J=11.7 Hz), 4.23 (s, 2H), 6.82 (dd, 2H, J=4.5, 7.5 Hz), 7.06-7.22 (m, 4H), 7.61 (d, 1H, J=7.8 Hz), 8.25 (d, 2H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.31, 25.55, 28.99, 50.64, 51.97, 58.01, 66.99, 74.20, 122.01, 127.92, 128.41, 130.02, 131.46, 131.98, 134.84, 138.05, 143.31, 146.84, 159.84, 167.91; ES-MS m/z 460 (M+H). Anal. Calcd. For C28H33N3O3: C, 73.18; H, 7.24; N, 9.14. Found: C, 73.07; H, 7.15; N, 9.16.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:14]([O:21][N:22]=[C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc2c1NC(=O)C2=O
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1NC(=O)C2=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a suspension of 4.91 g of 7-methylisatin in 100 ml of ethanol was added a solution of 5.59 g of O-benzylhydroxylamine hydrochloride and 3.29 g of sodium acetate in 40 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from benzene yielded 5.40 g (68%) of the title compound.
Reaction SMILES: CN(C)CCCN[C:7]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:11][CH:10]=1)=[O:8].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][OH:34].CCOCC>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][O:34][C:7]([C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCCNC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Reactant: CN(C)CCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCOC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1

Procedure:
The acid chloride (25 g) of Example 29 above was dissolved in THF (1250 ml) and 3-dimethylaminopropanol (250 ml) was added dropwise. After stirring overnight at room temperature ether (2 l) was added and the resulting precipitate was filtered. The crude ester (13.6 g) was purified via the hydrochloride salt, mp 288° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2].O1CCC[CH2:33]1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:21]([OH:23])=[O:22])[CH3:33])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:29][CH2:30]1)[CH3:27])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(C(C)C(=O)O)cc2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 125, 0.09 g, 0.21 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid foam (0.053 g, 61%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:17]Cl)[OH:16])=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:11][CH:10]=1
Reactant: OC(CCl)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a stirred suspension of 3.4 parts of a sodium hydride dispersion 78% in 90 parts of N,N-dimethylformamide are added portionwise, during a 5 minutes-period, 6.9 parts of 1H-1,2,4-triazole. After stirring for 10 minutes at room temperature, there are added 19.1 parts of 4-chloro-α-(chloromethyl)benzenemethanol. The whole is stirred and refluxed for 8 hours. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from methylbenzene, yielding 17.3 parts (77%) of α-(4-chlorophenyl)-1H-1,2,4-triazole-1-ethanol; mp. 119° C.