Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]3[C:13]([NH2:16])=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1.Cl>O>[NH2:16][C:13]1[C:12]2[C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:25]4[CH:24]=[C:23]([Cl:28])[N:22]=[C:21]([NH2:20])[N:26]=4)=[CH:3][C:4]=3[F:19])=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Agent: Cl
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)n1

Procedure:
100 mg (0.39 mmol) of 4-(4-amino-2-fluorophenoxy)-1,2-benzisoxazole-3-amine (from example VII) and 63.3 mg (0.39 mmol) of 2-amino-4,6-dichloropyrimidine are suspended in 3 ml of water, and 0.04 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a colorless precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=O)[NH:4][CH2:3][CH2:2]1.[Cl-:9].[NH4+:10]>>[ClH:9].[NH:10]=[C:5]1[CH2:6][CH2:7][O:1][CH2:2][CH2:3][NH:4]1
Reactant: [Cl-]
Reactant: O=C1CCOCCN1
Reactant: [NH4+]
Product: Cl
Product: N=C1CCOCCN1

Procedure:
Employing the procedure in Example 2, step D, tetrahydro-(2H)-1,4-oxazepin-5-one was reacted with Meerwien's salt and ammonium chloride to form hexahydro-5-imino-1H-1,4-oxazepine, hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=O.CC(O)=O.C[N:39](C)C=O>>[O:30]1[C:27]2[CH:28]=[CH:29][C:24]([C:10]3[CH:11]=[C:12]([C:14]4[CH:23]=[CH:22][C:21]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:15]=4)[N:39]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:25][C:26]=2[O:32][CH2:31]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.68 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MEOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 ml) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-naphthalen-2-yl-pyridin-2-yl)-phenol; mp 195-196° C.; 1H NMR (DMSO-d6) 6.17 (s, 2 H), 6.99 (m, 2 H), 7.17 (d, J=8.2 Hz, 1 H), 7.37 (m, 1 H), 7.63 (m, 2 H), 7.71 (dd, J=8.2, 1.9 Hz, 1 H), 7.83 (d, J=1.8 Hz, 1 H), 8.03 (m, 1 H), 8.12 (m, 2 H), 8.24 (dd, J=8.6, 1.8 Hz, 1 H), 8.35 (m, 2 H), 8.42 (d, J=1.1 Hz, 1 H), 8.74 (s, 1 H), 14.55 (s, 1 H); IR (KBr) 1605 cm−1; MS [M+H]+m/z=418. Anal. calcd for C28H19NO3: C, 80.56; H, 4.59; N, 3.36; Found: C, 80.13; H, 4.49; N, 3.18.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:1])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN(c1ccccc1)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 3 %

Procedure:
A solution of 3-(methyl(phenyl)amino)benzoic acid (0.056 g, 0.246 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.057 g; 0.246 mmol), HATU (0.102 g; 0.271 mmol) and N,N-diisopropylethylamine (0.106 mL; 0.616 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.003 g (3%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36](O)=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH2:72]([O:74][C:75]([CH:77]1[CH2:82][CH2:81][N:80]([CH:83]2[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]2)[CH2:79][CH2:78]1)=[O:76])[CH3:73]>C1COCC1.CCOC(C)=O>[CH2:28]([O:27][C:23]1[C:24]([CH3:26])=[CH:25][C:20]([CH2:19][C@@H:18]([O:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([N:8]3[CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[NH:3][C:2]3=[O:1])[CH2:14][CH2:13]2)=[O:16])[C:36]([N:86]2[CH2:87][CH2:88][CH:83]([N:80]3[CH2:81][CH2:82][CH:77]([C:75]([O:74][CH2:72][CH3:73])=[O:76])[CH2:78][CH2:79]3)[CH2:84][CH2:85]2)=[O:37])=[CH:21][C:22]=1[CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 400 mg (0.70 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g), 250 mg (0.78 mmol) TBTU and 0.12 mL (3.73 mmol) triethylamine in 20 mL THF were stirred for 1 h at RT. Then 0.4 mL (2.87 mmol) triethylamine and 270 mg (0.86 mmol) ethyl[1,4′]bipiperidinyl-4-carboxylate (used as the bis-hydrochloride salt) were added. The reaction mixture was stirred for 24 h at RT, diluted with EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (Alox activity stage II-III, gradient DCM/EtOH 40:1 to DCM/EtOH 30:1).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])C.Cl>C1COCC1.CCO.[Li+].[OH-]>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH:6]([CH3:16])[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)CC(C)Cc1ccccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1CC(C)CC(=O)O

Procedure:
A solution of 4-(2-methoxyphenyl)-3-methyl-butyric acid ethyl ester (24 mmol, crude from previous reaction) in THF (50 mL), EtOH (50 mL) and LiOH (1 M, 50 mL) was stirred at room temperature overnight. The reaction was acidified with 1 M HCl, and extracted with EtOAc. The combined extracts were washed with brine and dried over sodium sulfate. Concentration gave the desired product, which was used without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C12H16O3: 208.11. Found: 208.86
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][NH:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([N:43]4[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]4)=[O:42])[CH:35]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)=[O:23]>ClCCl>[CH3:20][NH:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:2]5[CH2:5][CH2:4][CH2:3]5)[CH2:45][CH2:44]4)=[O:42])[CH:35]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)=[O:23]
Reactant: C1CNC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
Azetidine hydrochloride (179 mg, 2.00 mmol) and sodium triacetoxyborohydride (434 mg, 2.05 mmol) were added to a dichloromethane (3.7 ml) solution of N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide (555 mg, 1.36 mmol) synthesized in Example 40, and stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure; and the residue was purified by use of silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The resultant was washed with a solvent mixture of ether-hexane=1:1; and the solid was filtered off to yield crystals of the title compound (5 mg), and a mixture (410 mg) including the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution, cooled to +5° C., of 2-hydroxyphenylacetic acid (1.06 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (2.23 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting 125-cc fractions. Fractions 4 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of acetonitrile (15 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Diphenyl-2-[(2-hydroxyphenyl)acetyl]perhydro-4-isoindolone (0.8 g) is obtained in the form of white crystals, m.p. 232° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:15][CH:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5].C(N(CC)CC)C.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH:16][C:38]([C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH:36]=2)=[O:39])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5]
Reactant: COC(=O)C1CC(N)c2c(Cl)cc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9) (300 mg, 0.963 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (403 μl, 2.89 mol) and the resulting mixture was stirred at room temperature for 5 min. To this was added 3-(tertbutyloxycarbonylamino)methyl benzoic acid (step a) (290 mg, 1.16 mmol), 1-hydroxybenzotriazole (156 mg, 1.16 mol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, 1.16 mmol) and stirring was continued for approximately 18 h. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and 0.5M citric acid (150 ml). The organic layer was retained and washed successively with 0.5M citric acid (150 ml), saturated sodium bicarbonate solution (2×150 ml) and brine (100 ml) before drying (Na2SO4). The solvent was removed and the residue was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (351 mg), m.p. 222°-223° C. δ (DMSO, 250 MHz) 1.39 (9H, s, C(CH3)3), 1.78 (1H, ddd, J=12.8, 12.6 and 3.9 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=12.8 Hz, CHACHBHCCHD), 3.71 (3H, s, COOCH3), 4.05 (1H, dd, J=13.0 and 3.0 Hz, CHACHBHCCHD), 4.14 (2H, d, J=5.8 Hz, ArCH2NH), 5.26 (1H, m, CHACHBHCCHD), 6.69 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.90 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.93 (1H, s, ArNHCH), 7.37 (3H, m, Ar-H and CH2NHCO), 7.71-7.76 (2H, m, Ar-H), 8.68 (1H, d, J=7.1 Hz); m/e 507 (M+), 198 (100%, M-H, CO2CH2CH3,NHCOC6H4CH2NHCOOC(CH3)3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1.C([OH:22])C.[Cl:23]C1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[ClH:23].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:22])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1
Reactant: CCO
Reactant: COc1cc(SC)ccc1-c1nc2cnccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(S(C)=O)ccc1-c1nc2cnccc2[nH]1
Product: Cl
Temperature: -35 °C

Procedure:
Two grams of 2-(2-methoxy-4-methylmercaptophenyl)imidazo[4,5-c]pyridine were dissolved in 50 ml. of hot ethanol and then cooled. One hundred milliliters of chloroform were added and the solution was cooled to -30 to -40° C. by means of an external cooling bath. A solution of 1.455 g. of 85% meta-chloroperbenzoic acid in 10 ml. of chloroform was added to the solution over a one hour period. The solution was stirred for three additional hours at -30 to -40° C. The reaction was then warmed to room temperature and evaporated in vacuo. The resulting foam was dissolved in 20 ml. of dimethylformamide after which were added 1.3 ml. of concentrated hydrochloric acid. Diethyl ether was added to the cloud point and the solution was stirred for 30 minutes. The suspension was then chilled and filtered affording 2.1 g. of the title product as brown crystals, m.p. about 210°-212° C.
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=O)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:64][C:65]1[CH:66]=[CH:67][C:68]2[N:72]=[C:71](C(O)=O)[NH:70][C:69]=2[CH:76]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:71]4[NH:70][C:69]5[CH:76]=[C:65]([Cl:64])[CH:66]=[CH:67][C:68]=5[N:72]=4)=[O:8])[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (20 mg, 0.066 mmol) in 1.5 mL of DMF is added TBTU (923.4 mg, 0.073 mmol), diisopropylethylamine (0.013 ml, 0.073 mmol) and 6-chloro-1H-benzoimidazole-2-carboxylic acid (prepared from literature in Eur.J.med.Chem. 1993, 28, 71) (14.3 mg, 0.073 mmol). The resulting mixture is left to stir at room temperature overnight. The crude mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (30.1 mg, 55%) is isolated as a white powder. C23H22ClN7O3 MS m/z: 480, 481. Anal. cald. for C23H22ClN7O3. 2C2HF3O2: C, 45.81; H, 3.42; N, 13.85. Found C, 45.19; H, 3.59; N, 13.76.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([CH2:23][NH:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:30])([CH3:3])[CH3:2].[CH3:31][C:32]([CH3:34])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:49]CCCl>>[ClH:49].[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([CH2:23][N:22]([CH:32]([CH3:34])[CH3:31])[CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][C:6]=1[CH3:30])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CC(C)=O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccccc2)O3)ccc1OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(C(C)C)CC(c2ccccc2)O3)ccc1OC(C)C
Product: Cl
Reaction time: 5 h
Yield: 36 %

Procedure:
To (4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone (30 mg, 0.07 mmol) and acetone (130 μL, 1.77 mmol) in DCE (0.5 mL) was added sodium triacetoxyborohydride (50 mg, 0.24 mmol) and the reaction mixture was stirred for 5 hours. The reaction mixture was concentrated in vacuo, diluted with methanol, microfiltered and purified by preparative LCMS (1-99% ACN/H2O, 5 mM HCl modifier) to give (4-isopropoxy-3-methyl-phenyl)-(10-isopropyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone hydrochloride salt (13 mg, 36%) as a glassy solid. ESI-MS m/z calc. 450.2. Found 451.5 (M+1)+; Retention time: 1.38 minutes (3 min run).
Reaction SMILES: [CH3:1][NH2:2].CO.CO.[C:7]([O:11][C:12]([N:14]([CH:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20]C)=[O:18])[CH3:15])=[O:13])([CH3:10])([CH3:9])[CH3:8].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[C:7]([O:11][C:12]([N:14]([CH3:15])[C@H:16]([C:22]([NH:2][CH3:1])=[O:24])[C:17](=[O:18])[O:19][CH3:20])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C(=O)OC(C)(C)C
Reactant: CN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 34 %

Procedure:
A 40% methylamine-methanol solution (67 mL) was added to a methanol (2.1 L) solution of diethyl [(t-butoxycarbonyl)(methyl)amino]propanedioate (Intermediate 3-1, 0.21 kg), and the mixture was stirred for 19 hours at room temperature. Further, a 40% methylamine-methanol solution (23 mL) was added, and the mixture was stirred for 4 days at the same temperature. Then, ethyl acetate (0.30 L) was added, and citric acid monohydrate (81 g) was slowly added under ice cooling, followed by stirring the mixture for 30 minutes under ice cooling. The precipitated solid was filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=75/25→15/85) to obtain N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, yellow oil) (63 g, 34%).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>[OH-].[K+]>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[SH:3]
Reactant: COc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(N)c(S)c1

Procedure:
To 2-amino-6-methoxy-1,3-benzthiazole (5 g, 0.027M) was added to a solution of potassium hydroxide (25 g in 50 ml of water). The mixture was heated at 140° for 5 hours. The crude 2-amino-5-methoxybenzenethiol produced was diluted with water (150 ml) and to this was added copper powder (1.25 g, 1 equivalent) and iodobenzoic acid (6.8 g, 1 equivalent). The mixture was heated under reflux for 4 hours under nitrogen. On cooling the mixture was filtered to remove copper, and acidified with concentrated hydrochloric acid. The solution was filtered to give the product as a light green solid (5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(OC)c2c1CCC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CCC(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one (670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (0.5 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-yl)amine (600 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([CH3:7])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17]CC)=[O:16])[CH2:3]1.CO.[OH-].[Li+].Cl>C1COCC1.O>[C:11]([O:10][C:8]([N:5]1[C@@H:6]([CH3:7])[C@@H:2]([CH3:1])[CH2:3][C@H:4]1[C:15]([OH:17])=[O:16])=[O:9])([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H]1C[C@H](C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)[C@H]1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of rel-(2S,4S,5S)-1-tert-butyl 2-ethyl 4,5-dimethylpyrrolidine-1,2-dicarboxylate in a mixture of THF (70 mL), MeOH (25 mL), and H2O (25 mL) was added lithium hydroxide (1.53 g, 63.7 mmol). The slurry was stirred at room temperature for 2.5 h and at 45° C. for 2 h. The solution was cooled to room temperature and HCl (aqueous, 1N, 70 mL) was added. The organics were concentrated and the resulting aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated to provide rel-(2S,4S,5S)-1-(tert-butoxycarbonyl)-4,5-dimethylpyrrolidine-2-carboxylic acid (3.08 g, 84%).