Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:9]Br)[C:2](CBr)=[CH:3][CH:4]=[CH:5][CH:6]=1.CNN.C[N:15]1C=C2[C:17](C=CC=C2)=[CH:16]1>O=O>[CH3:17][C:16]1[NH:15][C:2]2[C:1]([CH:9]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Cn1cc2ccccc2c1
Reactant: BrCc1ccccc1CBr
Agent: CNN
Agent: O=O
Product: Cc1cc2ccccc2[nH]1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A 2-liter 4-neck flask equipped with a dropping funnel, a stirrer, a thermometer, and a nitrogen-introducing inlet was charged with 15.0 g (0.057 mole) of o-xylylene dibromide, and this o-xylylene dibromide was dissolved in 150 ml of oxygen-removed anhydrous diethyl ether. Then, 10.5 g (0.23 mole) of methylhydrazine was dropped into the solution with stirring at 20° C. over a period of 30 minutes, and the mixture was stirred at room temperature for 12 hours. The formed white precipitate was recovered by filtration and a 20% aqueous solution of caustic soda, which had been subjected to the oxygen-removing treatment, was added to the recovered solid. The mixture was then stirred for 3 hours in a nitrogen atmosphere. Then, the formed suspension was extracted with 150 ml of chloroform and the chloroform solution was washed twice with 100 ml of water, and the chloroform solution was dried with potassium carbonate and concentrated under a reduced pressure. The formed yellow solid was placed in a sublimation device and heated on an oil bath under a reduced pressure, and 2.6 (0.020 mole) of 2-methylisoindole in the form of a white needle crystal was obtained at 85° C./10 mmHg in the bottom of a cooling zone of the sublimation device. When the nuclear magnetic resonance spectrum (1H-NMR) of the obtained product was determined in deuterated chloroform by using TMS as the internal standard, the following results were obtained:
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].Cl.N1C=CC=CC=1.[CH2:21]([O:23][C:24]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][CH3:34])=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[C:7]([O:35][CH:32]([CH2:33][CH3:34])[CH2:31][O:30][C:29]1[CH:36]=[CH:37][C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])=[CH:27][CH:28]=1)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc(OCC(O)CC)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(OCC(CC)OC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
In pyridine (10ml) 1.2 g (5 mmol) of 1-(p-ethoxycarbonyl-phenoxy)-butan- 2-ol was dissolved and to this solution was gradually added 0.6 g (5 mmol) of pivaloyl chloride cooling in an ice bath. The mixture was stirred at room temperature for 3 hours after the addition was completed. During the course of the reaction pyridine hydrochloride precipitated. The reaction mixture was then poured in ice water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to afford 1.6g of 1-(p-ethoxycarbonyl-phenoxy)-butan-2-ol pivalate (compound No. 1) in a yield of 89% as a light yellow viscous oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41]O)[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]([CH3:9])[CH2:7][CH3:8])[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Reactant: CCC(C)C(C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)C(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 2.06 g. of 2,3-dimethylvaleric acid (15.8 mmol). in 30 ml. of methylene chloride was cooled in a cold water bath and treated with 2.0 g. of oxalyl chloride (15.8 mmol.). The resulting solution was stirred at room temperature for 2 hours, then the methylene chloride was removed under reduced pressure. The resulting residue was added dropwise to a cold, stirred suspension of 1.2 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (3.1 mmol.) in 25 ml. of pyridine. After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate, which was collected, washed with water, air-dried, then purified using flash chromatography on silica gel, employing a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2,3-dimethyl-1-oxopentoxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a pale yellow crystalline solid (1.18 g; 76% yield) having the structural formula, ##STR22## a melting point in the range of 165°-173° C. and the following elemental analysis:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:25](=[O:27])[CH3:26])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(C)=O)cc2)c1C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of [4-(4-Amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and acetic anhydride (68.8 mg, 67 mmol) were mixed together under nitrogen and then pyridine (3 mL) was added to afford clear solution which was stirred for 10 minutes. The mixture was diluted with ethyl acetate (20 mL) and washed with 1.0 N HCl solution (10 mL), brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave [4-(4-acetylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (120 mg, 93.1%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.86 (s, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.46 (dd, J=8.8, 1.8 Hz, 1 H), 7.11-7.19 (m, 3 H), 3.95 (s, 2 H), 3.65 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H). HRMS calcd. for C22H19ClNO3 [(M−H)−.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[CH:21][CH:22]=1.CN([CH:27]=[O:28])C>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH:27]=[O:28]
Reactant: Fc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of n-BuLi (25 mL of 1.6 M solution in hexane, 40 mmol) in THF (100 mL) is added 2,2,6,6-teramethylpiperidine (6.8 mL, 40 mmol) at −78° C. and the mixture is stirred for 20 minutes. To this is added 3-bromofluorobenzene (7.0 g, 40 mmol). After stirring for 3 hours at −78° C., DMF (15 mL, 200 mmol) is added and the mixture is warmed to room temperature and stirred for 1 hour. The mixture is quenched with 1N HCl and extracted with EtOAc. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 10:1) to yield 2-bromo-6-fluoro-benzaldehyde. 1H NMR (CDCl3) 10.4 (s, 1H), 7.48-7.39 (m, 2H), 7.18-7.14 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyl ester (50 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H30N4O4, 499.23. found 499.4.
Reaction SMILES: N1(C2C=CC(C3N4CCC5NC(=O)C=CC(C=54)=CN=3)=C(C)C=2)CCOCC1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O:34]=[C:35]1[NH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:45]([C:48]4[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=4)=[N:46][CH:47]=[C:38]([C:39]=23)[CH:37]=[CH:36]1.[K+].[Br-]>CO.C(Cl)(Cl)Cl>[N:28]1([CH2:52][C:51]2[CH:54]=[CH:55][C:48]([C:45]3[N:40]4[CH2:41][CH2:42][C:43]5[NH:44][C:35](=[O:34])[CH:36]=[CH:37][C:38]([C:39]=54)=[CH:47][N:46]=3)=[CH:49][CH:50]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Agent: Cc1cc(N2CCOCC2)ccc1C1=NC=C2C=CC(=O)NC3=C2N1CC3
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1C=CC2=CN=C(c3ccc(CN4CCOCC4)cc3)N3CCC(=C23)N1

Procedure:
Using the reductive amination procedure described in Example 32, 0.097 g (38%) of 1-(4-morpholin-4-yl methyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one was prepared from morpholine and 4-(6-oxo-6,7,8,9-tetrahydro-2,7,9a-triaza-benzo[cd]azulen-1-yl)-benzaldehyde as a white solid: mp=285-286° C. (dec); Rf=0.11 (5% MeOH/CHCl3); IR (KBr) 1661, 1653, 1483, 1113 cm−1; 1H NMR (DMSO-d6) δ 2.40-2.41 (m, 4H), 3.15-3.17 (m, 2H), 3.26-3.61 (m, 6H), 4.45-4.46 (m, 2H), 7.35 (t, 1H, J=7.8 Hz), 7.51 (d, 2H, J=8.1 Hz), 7.82 (d, 2H, J=8.1 Hz), 7.84-7.90 (m, 2H), 8.43-8.47 (m, 1H). HRMS calcd for C21H22N4O2 362.1743 (M+), found 362.1737. Anal. (C21H22N4O2) C, H, N.
Reaction SMILES: [C:1]([NH:8][C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>C(N(CC)CC)C>[S:15]([OH:17])(=[O:22])(=[O:16])[CH3:14].[C:1]([NH:8][C:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)(C)OC(=O)NC1(CO)CC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added with a syringe and the contents stirred at room temperature overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4 filtered and evaporated to give N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.3 %

Procedure:
To a solution of (+)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Example 8, Step F (3.3 g, 16 mmol) in methylene chloride (100 mL) was added t-butyldimethylsilyl chloride (11 g, 49 mmol) and DIPEA (22 mL, 74 mmol). The reaction was stirred at rt for 16 h, poured into dilute aq. HCl and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford of (+)-trans-1-t-butyldimethylsilyloxymethyl-4-oxo-2-phenylcyclopentane (6.3 g) as a oil, [α]D=+97 (MeOH, c=0.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:14]/[O:15]CC(OC(C)(C)C)=O)/[C:9]([O:11][CH2:12]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+](C1C=C(/C(=N\O)/C(OC)=O)C=CC=1)([O-])=O>CO.[Pt](=O)=O>[NH2:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:14]\[OH:15])/[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1cccc(N)c1
Agent: O=[Pt]=O
Agent: COC(=O)/C(=N/O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)/C(=N/O)c1cccc(N)c1

Procedure:
Methyl (E)-3-amino-alpha-hydroxyiminophenylacetate can be obtained in the following manner: the reaction is carried out as in Example 9 for the preparation of ethyl (Z)-3-amino-alpha-tert-butoxycarbonylmethoxyimino-phenylacetate, but starting from 3.4 g of methyl (E)-3-nitro-alpha-hydroxyiminophenylacetate and 0.034 g of platinum dioxide in 20 cm3 of methanol. After treatment, 2.9 g of methyl (E)-3-amino-alpha-hydroxyiminophenylacetate are obtained in the form of a solid which is used as such in the subsequent syntheses.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:7]=1>CO.[Pd]>[ClH:4].[ClH:4].[CH2:1]([NH:3][CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1)[CH3:2]
Reactant: CCN
Reactant: ClCC1=NCC(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCNCC1NCC(c2ccccc2)c2ccccc21
Product: Cl

Procedure:
To a stirred solution of ethylamine (100 ml) in methanol (250 ml) maintained under nitrogen and cooled in an ice bath was added portionwise 1-chloromethyl-3,4-dihydro-4-phenylisoquinoline (10.0 g, 0.033 m) and the mixture heated to 50°-52° C. for 2 hours. After cooling, the solution was poured into a pressure bottle and hydrogenated on a Parr apparatus over 10% Pd/C catalyst (2.0 g) at 40 psi for 1 hour. The catalyst was removed by filtration and the solvent evaporated to a gummy residue. This residue was dissolved in methanol (50 ml) and isopropanol (50 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration. Recrystallization from methanol/isopropanol/water and vacuum drying gave 7.6 g of the major isomer of 1,2,3,4-tetrahydro-1-(ethylamino)methyl-4-phenylisoquinoline dihydrochloride, m.p. 241°-242°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:29].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[Br:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 0.603 mmol) in DCM (4 mL) and MeOH (2 mL) was added tetrabutylammonium tribromide (0.291 g, 0.603 mmol) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.267 g, 95%). LC/MS (Table 1, Method 2) Rt=1.217 min.; MS m/z: 467/469 [M+H]+.
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]5[N:37]=[C:38]([C@@H:41]6[CH2:46][C@@:45]7([CH3:47])[C@H:43]([CH2:44]7)[N:42]6C(OC(C)(C)C)=O)[NH:39][CH:40]=5)=[CH:32][CH:31]=3)[CH:24]=[CH:23]4)[N:19]=2)[CH2:13][C@@:12]2([CH3:55])[C@@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1.CO>[CH3:47][C@@:45]12[CH2:44][C@@H:43]1[NH:42][C@H:41]([C:38]1[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:14]7[CH2:13][C@@:12]8([CH3:55])[C@H:10]([CH2:11]8)[NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=1)[CH2:46]2
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(C)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5c[nH]c([C@@H]6C[C@]7(C)C[C@@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)cc2)c[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@]12C[C@@H](c3nc(-c4ccc(-c5ccc6cc(-c7c[nH]c([C@@H]8C[C@]9(C)C[C@@H]9N8)n7)ccc6c5)cc4)c[nH]3)N[C@H]1C2
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(1S,3S,5S)-3-(4-(4-(6-(2-((1S,3S,5S)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (250 mg. 0.344 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 231 mg). LC-MS retention time 3.09 min; Calcd. for C34H35N6: 527.29 m/z Found 527.35 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[ClH:7].[C:11]1([C:14]2([CH2:19][C:20]([NH2:21])=[NH:1])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a stirred suspension of NH4Cl (5.9 g, 111.97 mmol) in toluene (200 mL) was added trimethylaluminium (2 Min toluene) (56 mL, 111.96 mmol) at 5° C. The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. A solution of [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (321) (8.2 g, 37.32 mmol) in toluene (20 mL) was added to the reaction mixture at room temperature and the reaction mixture was heated at 80° C. for 14 h. After completion of the reaction, the reaction mixture was quenched with a suspension of silica gel (32 g) in chloroform (32 mL) at 0° C. The quenched mixture was stirred for 30 min at room temperature and filtered through a pad of celite. The residue was washed with methanol (5×50 mL) and the combined filtrate was concentrated. The residue was stirred in 10% methanol in dichloromethane (150 mL) and the resulting white solid was discarded by filtration and the filtrate was concentrated to get 2-(1-phenyl-cyclopentyl)-acetamidine, hydrochloride (322) (7 g, 79%, crude) as a yellow gummy oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[NH2:8])([CH3:3])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1>[CH:13]([O:12][C:10]1[CH:9]=[C:7]([NH:8][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc(N)cc(OC(C)C)c1
Solvent: CCN(CC)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc(OC(C)C)cc(OC(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
3,5-Diisopropyloxyaniline (2 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant mixture was dropwise added ethyl chloroformate (1.2 g) under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give ethyl N-(3,5-diisopropyloxyphenyl)carbamate (1.9 g) in a yield of 67.6%. M.P., 81.5°-82° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH:26][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COCCCN
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: COCCCNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=326.4 (M+H+), was prepared in accordance with the general method of example 3 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-methoxy-propylamine.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@@H:4]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6][NH:5]1.N1NN=NC=1C1C=CC=CC=1C1C=CC2N(C(CCCCCC)C(O)=O)C=NC=2C=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:10][O:9][C:7]1([O:11][CH3:12])[CH2:6][NH:5][C@H:4]([C:3]([OH:13])=[O:2])[CH2:8]1
Reactant: COC(=O)[C@@H]1CC(OC)(OC)CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: Oc1cccc2[nH]nnc12
Product: COC1(OC)CN[C@H](C(=O)O)C1

Procedure:
4,4-Dimethoxy-L-proline methyl ester (1.35 mmoles, 0.257 g) and 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.23 mmoles, 0.5 g) were reacted in the presence of hydroxybenzotriazole and dicyclohexylcarbodiimide as in Example 15 to yield 0.220 g of 1-[1-Oxo-2-[5-2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octyl]-4,4-dimethoxy-L-proline. (MS) .
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1)[CH3:22]
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Reactant: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C)cc(C(=O)O)n1

Procedure:
A solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (265 mg, 1.54 mmol) and Hünig's base (0.8 mL) in ethanol (1.79 mL) is stirred at 70° C. for 24 h. Ethanol is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C., concentrated and purified by prep. HPLC (X-Bridge) to give 2-ethoxy-6-methyl-pyrimidine-4-carboxylic acid (201 mg) as a yellow solid; LC-MS: tR=0.63 min, [M+H]+=183.04.