Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCCCCCCOc1cc(C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of 5-(9-methoxycarbonyl-nonyloxy)-isophthalic acid di-tert-butyl ester (162 mg, 0.34 mmol) in THF (2 ml) was added 1 N NaOH (0.35 ml). The mixture was refluxed for 7 h. The mixture was left at room temperature over night before concentration. To the residue EtOAc and 0.1N HCl was added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([C@H:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH2:4][O:3]1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O.CCOCC>[Si:17]([N:10]1[C@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][C:9]1=[O:11])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H]([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)O1
Reaction time: 2 h

Procedure:
A solution, cooled to 0°, of 17.1 g (0.1 mmol) of (S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and 15.1 g (0.1 mol of t-butyldimethylchlorosilane in 100 ml of dimethylformamide is treated while stirring with 10.6 g (0.105 mol) of triethylamine, whereby a precipitate results immediately. The mixture is stirred at 0° for 2 hours, then diluted with 200 ml of ether and the reaction mixture is washed five times with 80 ml of water each time. The aqueous phases are then extracted with 100 ml of ether. The organic phases are dried over sodium sulphate and evaporated, whereupon the residual oil is distilled. There is obtained (S)-1-(t-butyldimethylsilyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone of boiling point 84°-87° (0.5 Torr); [α]D20 =-22.7° (c=1, ethyl acetate).
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>CCO>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[NH:8][C:11](=[O:12])[C:10]([F:17])([F:16])[F:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: CCO
Product: N[C@H]1CCCC[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
cis-Cyclohexane-1,2-diamine (5.00 g, 43.9 mmol, 1.00 eq) was charged to a 250 ml, three-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Ethanol (50 mL) was added and the solution was cooled to <0° C. using an ice-brine bath. A solution of ethyl trifluoroacetate (6.23 g, 1.00 eq) in EtOH (25 mL) was added via a syringe pump over a one hour period. Once the addition was complete, the cooling bath was removed and the solution was slowly warmed to RT and stirred for 3.5 hours to afford the title compound in EtOH. Half (41 mL, about 21.9 mmol) of the total solution (about 82 mL) was carried into the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([O:23]CC4C=CC(OC)=CC=4)=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]/[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 10.1 %

Procedure:
A stirred solution of 4-methoxybenzyl (6R,7R) -7-phenylacet-amido-3-(1-propenyl)-ceph-3-em-4-carboxylate (0.509 g, purity 9% E-isomer, 84% Z-isomer, 0.99 mmol) in dichloromethane (15 ml) was cooled to 2° C. Titanium tetrachloride (0.5 ml, 4.5 mmol) was added in 1 min. After 30 min the brown suspension was mixed with a chilled mixture of dichloromethane (50 ml) and a 2M solution of hydrochloric acid in water (50 ml). The organic phase was separated and extracted with a 2M solution of hydrochloric acid in water (3×50 ml). The aqueous phases were extracted with dichloromethane (25 ml). The combined organic phases were analyzed using HPLC: 0.036 g (6R,7R)-7-phenylacetamido-3-[(E)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.10 mmol, yield 10.2%); 0.301 g (6R,7R)-7-phenylacetamido-3-[(Z)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.84 mmol, yield 84.8%). The overall yield is therefore 95.0%.
Reaction SMILES: [C:1]([N:8]1[CH:13]([C:14](=[O:22])[C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:20][C:16]([CH3:19])([CH2:17][CH3:18])[C:15](=[O:21])[C:14]([CH:13]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: Ic1cccnc1
Reactant: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2-hex-5-ynoylperhydropyridazinyl)-3,3-dimethylpentane-1,2-dione (0.384 g, 1.25 mmol) in 10 ml CH2Cl2under nitrogen was added 3-iodopyridine (0.283 g, 1.38 mmol), (Ph3P)2PdCl2 (0.044 g, 0.06 mmol), CuI (0.0024 g, 0.013 mmol) and triethylamine (0.3 ml, 2 mmol). The reaction mixture was stirred 30 minutes at room temperature and then refluxed overnight. The mixture was concentrated and purified by silica gel column, eluting with 30% ethyl acetate in hexane, to yield product as light yellow oil (0.31 g, 65%). 1H NMR (CDCl3, 400 MHz) δ 0.84 (t, 3H, J=7.4); 1.21 (s, 6H); 1.70 (m, 6H); 1.96(m, 2H), 2.52 (m, 3H); 2.90 (m, 2H); 3.60 (m, 1H); 4.42 (m, 2H); 7.20 (m, 1H); 7.66 (m, H); 8.49 (m, 1H); 8.62 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9].[N+:14]([C:17]1[CH:22]=CC=CC=1S(Cl)(=O)=O)([O-])=O.[CH2:27]([NH2:29])[CH3:28]>>[NH:14]1[CH2:17][CH2:22][N:29]=[C:27]1[CH2:28][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN
Reactant: CCNS(=O)(=O)c1ccccc1N
Product: CCNS(=O)(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-ethylbenzenesulfonamide (prepared from 2-nitrobenzenesulfonyl chloride and ethylamine using the methods described in Example 50) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-ethylbenzenesulfonamide, isolated as the fumarate salt.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:16][C:17]([O:19]CC)=[O:18])[C:4]=2[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:16][C:17]([OH:19])=[O:18])[C:4]=2[CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)O)CN(C)CC1
Temperature: 75 °C
Yield: 21 %

Procedure:
Ethyl 2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate (0.35 g, 1.2 mmol) in THF (10 mL) was added to a solution of sodium hydroxide (0.146 g, 3.6 mmol) in water (3 mL) and heated at 75° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed; water (10 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2×10 mL). The pH of aqueous layer was adjusted to 2-3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was evaporated, the residue was extracted with methanol, filtered, the filtrate was concentrated under reduced pressure to yield 2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetic acid (65 mg). 1H NMR (CD3OD): 7.30 (s, 1H) 7.20 (d, 1H), 7.0 (d, 1H), 5.1 (d, 1H), 4.8 (d, 1H), 4.18 (m, 1H), 4.0 (s, 2H), 3.81 (m, 1H), 3.42 (s, 3H), 3.15 (bs, 2H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][SnH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([OH:15])=[O:14].[H][H]>C1(C)C(C)=CC=CC=1.COC>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([O-:15])=[O:14].[CH3:1][Sn+:2]([CH3:4])[CH3:3]
Reactant: O=S(O)c1cc(Cl)ccc1Cl
Reactant: C[SnH](C)C
Reactant: [H][H]
Agent: COC
Solvent: Cc1ccccc1C
Product: C[Sn+](C)C
Product: O=S([O-])c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 ml three-necked flask, fitted with a reflux condenser and addition funnel, was flushed thoroughly with nitrogen and charged with 4.5 ml (29.5 mmoles) of a solution of trimethyltin hydride in xylene (78 volume/volume %). To this solution was added dropwise with stirring at room temperature 70 ml of a solution of 6.0 g (28.5 mmoles) of 2,5 -dichlorobenzenesulfinic acid in dimethyl ether. Evolution of hydrogen occurred immediately and throughout the addition which lasted one hour. The flask was cooled in ice-water, and 9.38 g of solid was collected on a filter. The solid was recrystallized from cyclohexaneligroin giving 9.28 g of trimethyltin 2,5 -dichlorobenzenesulfinate, m.p. 126.3°-128.8° C. The presence of strong absorption bands at 950 and 980 cm-1, characteristic of the ##STR21## group in organotin sulfinates, was observed in the infrared spectrum (KBr). The NMR spectrum showed the following characteristics: The aromatic proton ortho to the sulfinato group appeared as a multiplet centered at 765 Hz (1 proton); the remaining aromatic protons appeared as a multiplet centered at 727 Hz (2 protons); the protons of the trimethyltin group appeared as a singlet at 62 Hz flanked on either side by two satellite bands (9 protons).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][NH2:12].[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[N:12]([CH3:11])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][CH:9]=[N:10][C:2]=5[N:1]=4)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=Cc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Reactant: CN
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2ncccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-aminonicotinic acid, methylamine and 4-[(1-cyclopentyl-4-piperidinyl)oxy]benzaldehyde. The obtained compound was recrystallized from diethyl ether to give a pale yellow acicular crystal (m.p. 175.0-177.2° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=4[Cl:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)cc4Cl)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2,4-dichlorophenylboronic acid (164 mg, 0.86 mmol) the subtitle compound was obtained, (148 mg, 62%). 1H NMR (DMSO) δ 8.69(s, 1H), 8.51(d, 1H), 7.93(d, 1H), 7.84(s, 1H), 7.60(m, 3H), 4.12(s, 3H). MS 415 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:19][C:20]#[N:21])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:20]([CH2:19][N:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])[N:7]=2)=[CH:9][CH:10]=1)[S:15]([CH3:18])(=[O:17])=[O:16])#[N:21]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)c(C(=O)O)c3)n2)cc1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
N-(4-(2-chloropyrimidin-4-yl)phenyl)-N-(cyanomethyl)methanesulfonamide (171 mg, 0.53 mmol), 5-amino-2-morpholinobenzoic acid (142 mg, 1.2 eq.) and p-toluene sulfonic acid monohydrate (98 mg, 0.98 eq.) were suspended in 1,4-dioxane (8 mL) and heated at 100° C. overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was taken up in ethyl acetate (80 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was then dried and concentrated in vacuo. The residue was repeatedly triturated with methanol (5 mL then 3 mL) to afford, as a cream solid, 5-(4-(4-(N-(cyanomethyl)methylsulfonamido)phenyl)pyrimidin-2-ylamino)-2-morpholinobenzoic acid (101 mg, 37%). 1H NMR (300 MHz, d6-DMSO) δ 17.23 (1H, s) CO2H, 9.99 (1H, s); 8.74 (1H, d, J=2.7 Hz); 8.62 (1H, d, J=5.0 Hz); 8.33 (2H, d, J=8.7 Hz); 8.01 (1H, dd, J=2.8, J=8.7 Hz); 7.69 (1H, d, J=9.1 Hz); 7.63 (2H, d, J=8.7 Hz); 7.52 (1H, d, J=9.1 Hz); 4.97 (2H, s); 3.81 (4H, m); 3.21 (3H, s); 3.06 (4H, m). LC-ESI-MS (method C): rt 5.4 min.; m/z 509.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(C(N)C2CCCCC2)CCCCC1.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:9]=2)[CH:5]=[C:4]([CH2:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)C=CCc1cc(C)c2[nH]ncc2c1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C=CCc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To the clear solution of ethyl 4-(7-methyl-1H-indazol-5-yl)but-2-enoate (760 mg, 3.11 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was added dicyclohexylmethyl amine (2.6 mL, 6.2 mL, 2.0 equiv) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.73 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between 0.5 N sodium hydroxide and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual colorless oil was purified by flash column chromatography (20% ethyl acetate in hexanes) to afford the desired product as a colorless oil (1.08 g, 93%). MS (ESI) [M+H]+=375.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:12]=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:14]([NH2:16])[CH3:15].C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[C:3]([CH2:12][NH:16][CH2:14][CH3:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1nc2ccccc2cc1Br
Reactant: CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1nc2ccccc2cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-quinoline-2-carbaldehyde (3.34 g, 16.3 mmol), ethylamine (2M in MeOH; 9.78 mL, 19.6 mmol), and acetic acid (1.02 mL, 17.8 mmol) were combined in MeOH (25 mL) and stirred at 0° C. for 30 minutes. Sodium cyanoborohydride (1.53 g, 24.5 mmol) was added, and the reaction was monitored by analytical LCMS. The mixture was worked-up with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]([CH:5]([C:12]([OH:14])=[O:13])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH:15]1([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]([OH:14])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCCCC1
Reactant: CC(C)(C)C(C[C@H](N)C(=O)O)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)C(C[C@H](NC1CCCCCCC1)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a stirred suspension of γ-tert-butyl-L-glutamic acid (4.06 g, 20.0 mmol) and cyclooctanone (3.15 g, 25 mmol) in N,N-dimethylformamide/acetic acid (99:1, v/v, 50 mL) was added sodium triacetoxyborohydride (6.36 g, 30.0 mmol) in small portions and the mixture was stirred overnight. After evaporation of the solvent, the residue was dissolved in water (50 mL). The pH was adjusted to 9 with 2 N sodium hydroxide solution, followed by extraction with diethylether (50 mL). Subsequently, the pH of the aqueous layer was carefully adjusted to 2.5 using 1.0 N hydrochloric acid. Extraction with dichloromethane afforded an organic layer, which was dried (magnesium sulphate) and concentrated under reduced pressure, yielding 4.82 g (77%) of the title compound as a white solid. ESI-MS: 314.2 (M+H)+, 336.2 (M+Na)+. Rf (silica gel; ethyl acetate/pyridine/acetic acid/water 63:20:6:11, v/v): 0.80.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:19]([O:20][CH3:21])=[CH:18][C:12]2[S:13][C:14]([CH:16]=O)=[CH:15][C:11]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C-:34]#[N:35].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:7][O:8][C:9]1[C:19]([O:20][CH3:21])=[CH:18][C:12]2[S:13][C:14]([CH:16]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:34]#[N:35])=[CH:15][C:11]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: [C-]#N
Reactant: COc1cc2cc(C=O)sc2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2cc(C(C#N)N3CCOCC3)sc2cc1OC
Temperature: 25 °C

Procedure:
Morpholine (10.8 ml) was added to a stirred suspension of 5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde (5.0 g) and p-toluenesulphonic acid monohydrate (4.3 g) in dry dioxan (43 ml) under an atmosphere of nitrogen. The mixture was heated at reflux for 30 min. and then the resultant solution was cooled to 50° C. and treated in one portion with a suspension of potassium cyanide (1.46 g) in water (2.5 ml). The reaction mixture was heated at reflux for 1 hour then cooled to room temperature and treated with 15% w/v potassium carbonate in water (20 ml). The reaction mixture was then diluted with water (200 ml) and the resultant precipitate was filtered and dried to give 2-(5,6-dimethoxy-benzo[b]thien-2-yl)-2-(4-morpholinyl)acetonitrile as a pale yellow solid (6.54 g). A portion crystallized from dichloromethane/diethyl ether had m.p. 196°-199° C.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47]C(OC(C)(C)C)=O)[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[ClH:55]>C(#N)C>[ClH:55].[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH2:47])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:43])([CH3:42])[CH3:44])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][CH:20]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C

Procedure:
Under a nitrogen atmosphere, 1.37 g (1.84 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S) -hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane are stirred in 64 ml of acetonitrile and 64 ml of aqueous 2N HCl at room temperature for 6 days. The reaction mixture is filtered, and the filtrate is concentrated by evaporation under a high vacuum at room temperature and is finally lyophilised from dioxane to yield the title compound: HPLC20-100 : tret =14.2; 1 H-NMR (CD3OD) inter alia δ 8.10 (d, J=8, 2Harom), 7.8 (m, 1Harom), 7.53 (m, 2Harom), 7.32 (m, 3Harom), 7.17 (m, 6Harom), 2.23 (s, 2 H3Ctetrazole-protecting group).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]=[N+]=[N-])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][NH2:35])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN=[N+]=[N-])c3)c2)Cc2ccccc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
The compound of step 1 (0.185 g, 0.360 mmol) and triphenylphosphine (0.149 g, 0.539 mmol) were dissolved in a mixture of 3 ml of THF and 3 ml of water, and the solution was stirred overnight at room temperature. The mixture was evaporated to dryness and purified by silica gel chromatography (DCM/methanol/28% ammonia gradient, 70:30:0 to 0:100:0 to 0:90:10) to yield 0.17 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1.O.[NH2:23][NH2:24]>O1CCCC1>[NH:23]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1)[NH2:24]
Reactant: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1

Procedure:
A solution of 2-((1R,2R)-2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-6, 200 mg, 0.0.669 mmol, 1.0 eq) and hydrazine hydrate (335 mg, 6.69 mmol, 10 eq) in tetrahydrofuran (3 mL) was heated by microwave irradiation at 80° C. for 40 minutes. The reaction mixture was filtered and concentrated to dryness. The afford 2-((1R,2R)-2-(6-hydrazinyl-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-7) as a glassy yellow solid. LRMS m/z (M+H) 294.4 found, 294.2 required.