Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[CH3:29]I.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][O:25][CH3:29])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(-c2nn(C)c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
4-(7,8-Dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (17 mg, 44 μmol) is dissolved in N,N-dimethylformamide (2.1 ml) under argon, and methyl iodide (8.2 μl, 131 μmol) and sodium hydride (95%, 2.4 mg, 96 μmol) are subsequently added. The reaction solution is stirred at 0° C. for 2 h. After addition of a little water, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution for work-up. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-methoxymethylbenzonitrile (4 mg, 10.3 μmol) as a colourless solid. MS: 389.2 (M+H+), TLC (HPTLC): Rf=0.41 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:26])/[CH:20]=[C:21](\[CH3:25])/[CH:22](Cl)[CH3:23]>CN(C=O)C>[CH3:17][O:18][C:19](=[O:26])/[CH:20]=[C:21](\[CH3:25])/[CH:22]([S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH3:23]
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: COC(=O)/C=C(\C)C(C)Cl
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\C)C(C)Sc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-pentenoic acid methyl ester (1.00 g, 6.94 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (2.47 g, 7.63 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 75 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 75/25) and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester (0.19 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×15 ml). The extracts are combined, washed with saline (15 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (85/15). The appropriate fractions are combined (Rf =0.18, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 124-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(NC(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NC(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-acetamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound: Rf=0.18 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[O:17]=[C:11]([CH2:9][C:8](=[O:10])[C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccncc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.466 g, 20.26 mmol), 1-(4-pyridinyl)ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (2.388 mL, 17.62 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (24%). LCMS E-S (M+H)=222.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.55 (m, 3 H), 4.43 (q, J=7.07 Hz, 2 H), 7.06-7.16 (m, 1 H), 7.72-7.92 (m, 2 H), 8.82-8.94 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Product: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized according to Example 61A using 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile and allyl bromide: 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.8, 2.6 Hz, 1H), 5.80 (ddt, J=17.2, 10.4, 5.0 Hz, 1H), 5.31 (app. d, J=10.6 Hz, 1H), 5.14 (app. d, J=17.2 Hz, 1H), 4.19-4.11 (m, 2H), 3.98 (q, J=8.6 Hz, 2H); MS (APCI) m/z 309 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[CH:35]1
Reactant: O=Cc1ccoc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(Cc2ccoc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 8.6 mg of (1R)—N-{[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1c(N)cccc1Cl

Procedure:
2-Amino-6-chlorobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-amino-6-chlorobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Br:11]Br>CC(O)=O>[Br:11][CH:4]1[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8]
Reactant: BrBr
Reactant: CC1(C)CCC(=O)CC1=O
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)C(Br)C1=O

Procedure:
To a stirred solution of 4,4-dimethylcyclohexane-1,3-dione (1.4 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid which was used without further purification. LCMS (ES+) 218.9 (+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)(=[O:4])=[O:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:5]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(NS(C)(=O)=O)oc23)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O

Procedure:
This compound is prepared in the manner of Step F, Example 1, with 4.3 grams (10 mmole) of 3-(2-methylsulfonylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 1.5 grams (11 mmole) of potassium carbonate, 1.7 grams (12 mmole) of methyl iodide, and 25 mL of acetone as reagents.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH:15]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[C:30](O)[CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[N:25][N:26]=3)[CH:23]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[C:30]([O:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[N:25][N:26]=3)[CH:23]=2)[CH2:17][CH2:16]1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2cccc(Cl)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
707 mg of N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine was dissolved in 8.00 mL of DMF, and 302 mg of 4-methoxybenzylamine, 324 mg of HOBt, and 460 mg of WSC were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 881 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)-N2-[(4-methylphenyl)sulfonyl] glycinamide.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:10])[CH3:9].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([C:8](=[O:10])[CH3:9])(=[O:19])=[O:18]
Reactant: CCO
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)S(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of triethylamine (0.86 g, 8.51 mmol, 2.2 equiv.) in dichloromethane (3 mL) at 0° C. was added ethanol (0.18 g, 3.87 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride (0.83 g, 4.65 mmol, 1.2 equiv.). After stirring for 4 hours at 0° C., the solution was concentrated under reduced pressure. The concentrate was dissolved in aqueous NaHCO3 solution (50 mL) and extracted with diethyl ether (3×50 mL). The ether extracts were combined and washed with aqueous NaCl (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (5% EtOAc/Hex) afforded 16 (95%): 1H NMR (CDCl3, 400 MHz) δ 8.70 (d, J=4.7 Hz, 1H, ArH), 7.95 (p, J=6.4 Hz, 2H, ArH), 7.56 (t, J=5.3 Hz, 1H, ArH), 4.37 (q, J=7.0 Hz, 2H, CH2OSO2R), 1.29 (t, J=7.0 Hz, 3H); MALDI-FTMS 188.0000 (C6H9NOS+H30 requires 188.0376).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH3:25]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH3:25]
Reactant: CCCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using propyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as an amorphous tan solid. 1H NMR (CDCl3, 300 MHz) δ 0.94 (t, 2H), 1.40-2.01 (m, 6H), 2.65-2.70 (t, J=9.6 Hz, 2H), 2.70-2.95 (m, 2H), 2.95-3.45 (m, 7H)), 3.3.60-3.95 (m, 1H), 6.37(d, J=7.7 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.6 Hz) ppm. MS (CI): 258 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][C:19]([O:33][CH3:34])=[C:20]([O:31][CH3:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[ClH:35].[CH3:32][O:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:33][CH3:34])[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCOCC3)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc2nc(NC3CCNCC3)nc(N3CCOCC3)c2cc1OC

Procedure:
A solution of 4-(6,7-dimethoxy-4-morpholin-4-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.45 g, 5.18 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 374.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[O:25])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried to obtain 3-nitrobenzoyl chloride as a yellow solid. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. Then 3-nitrobenzoyl chloride prepared above (3.34 g, 18 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The solvents was evaporated under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, the solid was washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(3-nitrobenzeneamido)benzoic acid as a yellow solid (1.8 g, yield 100%). LC-MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].O.[N:11]([O-])=O.[Na+]>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: Nc1cc(I)cc(I)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)cc(I)c1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
3,5-Diiodoaniline was obtained by the procedure of M. Bérubé (M. Bérubé, et al. Synthesis of Simplified Hybrid Inhibitors of Type 1 17β-Hydroxysteroid Dehydrogenase via the Cross-Metathesis and the Sonogashira Coupling Reactions, Organic Lett. 6 (2004) 3127-3130). 5 g (14.5 mmol) of 3,5-diiodoaniline were stirred with the solution of 5 mL of concentrated hydrochloric acid and 5 mL of water. The mixture was cooled to about −10° C. and 5.5 mL of 20% aqueous solution of NaNO2 was added dropwise with continuous stirring. The suspension was allowed to stir for another 40 minutes. Next, the cooled solution of 10.8 g (47.9 mmol) of SnCl2-2H2O in 11 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept −10° C. for one hour and at 5° C. overnight. The obtained precipitate of a double salt with tin chloride was filtered off and washed with water. The residue was resuspended in water and added concentrated aqueous solution of NaOH to alkaline medium. The 3,5-diiodophenylhydrazine was extracted with ether, the organic layer was washed in turn with aqueous NaOH, Na2S2O3 and water, and dried with CaCl2. Ether was evaporated to give 4.2 g of 3,5-diiodophenylhydrazine. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.10 (2H, d, 1.2 Hz, arom.), 6.92 (1H, d, 1.2 Hz, arom.), 5.51 (1H, s, NH), 4.12 (2H, broad s, NH2).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[OH:4].[K+].[Br-]>O.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3](=[O:4])[CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1
Reactant: COc1cc(O)c(Br)cc1O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC1=CC(=O)C(Br)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred solution of NaIO4 (7.81 g, 36.5 mmol, Baker) in H2O (200 mL) there was added a solution of 2-bromo-5-methoxyhydroquinone (4.00 g, 18.3 mmol) in CHCl3 (150 mL, prepared with warming). The reaction immediately turned dark and then became orange over a period of time. The reaction was allowed to stir at rt for 30 min. The layers were separated and the aqueous portion extracted with CHCl3 (1×30 mL). The combined CHCl3 portion was washed with brine (1×30 mL), filtered through cotton, and the solvent removed in vacuo to give a mustard yellow solid (4.0 g, 100%, pure by TLC); mp 184°-186° C. Crystallization of a 50 mg sample from MeOH (dissolved in 5 mL of MeOH, allowed to cool to rt) yielded orange needles (43 mg, 86% recovery); mp 186°-187° C., lit 190°-191° C. (Blatchly, J. M.; Green, R. J. S.; McOmie, J. F. W.; Searle, J. B. J. Chem. Soc. (C),1353-1355 (1969)); 1H NMR (CDCl3) δ3.86 (s, 3H), 6.12 (s, 1H), 7.24 (s, 1H); IR (KBr) 3044 (m), 1669 (s), 1649 (s), 1623 (s), 1584 (s), 1197 (s), 1169 (s).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:8]1([C:18](O)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[C:8]1([C:18]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCNC1
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: O=C(c1cccc2ccccc12)N1CCCNCC1
Reaction time: 8 h

Procedure:
Homopiperazine (0.60 g, 6.0 mmol), naphthalene carboxylic acid (0.51 g, 3.0 mmol), 1-hydroxybenzotriazole (0.45 g, 3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (0.63 g, 3.3 mmol) were added to dry, degassed dimethylformamide (7 mL). The pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred overnight. The dimethylformamide was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel using chloroform/methanol as eluant and the title compound was isolated (0.100 g). NMR (CDCl3, 300 MHz) d 7.88 (2H, m), 7.50 (3H, m), 7.27 (1H, m), 4.08 (1H, m), 3.81 (1H, m), 3.28 (2H, m), 3.18 (1H, m), 3.00 (1H, m), 2.92 (1H, t, J=7 Hz), 2.72 (1H, t, J=7 Hz), 2.20 (1H, m), 1.58 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1

Procedure:
To a solution of 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (5.0 g) in dimethylformamide (DMF) (25 ml) was portionwise added sodium hydride (60% in oil) (1.29 g) with stirring under ice-cooling. The mixture was successively stirred at ambient temperature for 30 minutes, stirred at 60° C. for 1 hour and cooled with an ice bath. To the reaction mixture was added 1,5-dibromopentane (6.72 ml), and the mixture was stirred at ambient temperature for 3 hours. The reaction solution was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate (80 ml) and n-hexane (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-bromopentyloxy)-1-N-t-butoxycarbonylpiperidine (2.44 g).