Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:45][O:46][CH3:47])[C:30]([NH:32][CH:33]2[C:43](=[O:44])[N:35]3[C:36]([C:40]([OH:42])=[O:41])=[CH:37][CH2:38][S:39][C@H:34]23)=[O:31])[N:28]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:45][O:46][CH3:47])[C:30]([NH:32][CH:33]2[C:43](=[O:44])[N:35]3[C:36]([C:40]([O:42][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41])=[CH:37][CH2:38][S:39][C@H:34]23)=[O:31])[N:28]=1
Reactant: CCCCCCCCOCC(CI)OCCCCCCCC
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCCOCC(COC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12)OCCCCCCCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
To a stirred solution of 2,3-di-n-octyloxypropyl iodide (529 mg) in dimethylsulfoxide (14 ml) was added 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1427 mg) and triethylamine (0.52 ml) at room temperature, and stirred at 40° C. for 4 hours and at 50° C. for 4 hours. The resultant mixture was poured into ice water (200 ml), adjusted to pH 8 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate (140 ml). The extract was washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After washing the residue with n-hexane (8 ml), the residue was tritulated with petroleum ether and then the precipitates were collected by filtration to give 2,3-di-n-octyloxypropyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 160 mg), mp. 75° to 78° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Yield: 34.1 %

Procedure:
A mixture if 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was wash washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (99.7 mg, 34.0%) as a solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Na+].[I-].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][C@H:18]4[CH2:24][CH2:25][N:49]([CH:46]5[CH2:48][CH2:47]5)[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCN(C4CC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added NaI (62 mg, 0.41 mmol) and cyclopropylamine (56 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the racemic product (91 mg, 42%). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-cyclopropyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ column eluting with methanol at a flow rate of 60 mL/min. 91 mg of racemic material was separated in 1 injection of 5 mL at 18 mg/ml in methanol to afford the product which eluted after its enantiomer (29 mg, 13%). 1H NMR δ (300 MHz, CDCl3) 0.66-0.91 (m, 4H), 2.14 (sextet, 1H), 2.35 (quintet, 2H), 2.48-2.62 (m, 4H), 2.66-2.78 (m, 1H), 3.27-3.49 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.92 (t, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); m/z 529 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.Cl[S:27]([C:30]1[C:38]2[C:34](=[N:35][S:36][N:37]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=CC=1.NCCN(CCN)CCN>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:27]([C:30]1[C:38]2=[N:37][S:36][N:35]=[C:34]2[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of (S)-2-(2-amino-4-iodo-benzoylamino)-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (39 mg, 0.079 mmol) in DCM (1 mL) was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (37 mg, 0.158 mmol) and pyridine (30 μL, 0.371 mmol). The mixture was shaken overnight at rt, then polymer bound tris(2-aminoethyl)amine resin was added. The resulting mixture was shaken for 2 h, and the resin was removed by filtration and rinsed with DCM. TBD methyl polystyrene resin was then added and the mixture was shaken for 2 h. The liquid was drained and the resin was washed with DCM (3×). A solution of 10% TFA in DCM (3 mL) was added to the resin and the mixture was shaken for 1.5 h. The resin was removed by filtration, washed with 10% TFA in DCM and the filtrate was concentrated to provide the desired product as a white solid (55 mg, 99%). 1H NMR (400 MHz, CDCl3): 11.10 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 8.02 (d, J=1.5, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.37-7.32 (m, 2H), 7.16 (d, J=2.0, 1H), 6.96 (d, J=8.3, 1H), 6.92 (dd, J=8.2, 2.0, 1H), 6.67 (d, J=7.3, 1H), 4.96 (q, J=5.7, 1H), 3.83 (s, 3H), 3.20-3.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]#[C:21][C:22]2[CH:27]=[CH:26]N=[CH:24][CH:23]=2)[CH:19]=1)=[O:13].O1CCC[CH2:35]1>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:35]=[CH:24][CH:23]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#Cc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(CCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a suspension of palladium on carbon (0.063 g, 0.059 mmol) in ethanol (1 mL) under nitrogen was added N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.13 g, 0.295 mmol) and then ethanol (5 mL) and tetrahydrofuran (THF) (1.5 mL). The suspension was stirred under an atmosphere of hydrogen (ca. 1 atm, balloon) overnight. The reaction mixture was then evacuated with nitrogen, and diluted with 10% MeOH/DCM. Celite was added and the contents stirred for 15 min., and then filtered through Celite (analytical grade) and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluent: gradient of 5-95%. Dichloromethane/Chloroform containing 10% 2M ammonia (in methanol). The collected solid was dried in vacuum oven at 45° C. for 18 h. The final product was collected as 0.112 g (84%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.21 (s, 3H), 3.08-3.18 (m, 2H), 3.22-3.29 (m, 2H), 4.36 (d, J=5.05 Hz, 2H), 5.18 (quin, J=6.69 Hz, 1H), 5.90 (s, 1H), 7.28 (d, J=6.06 Hz, 2H), 7.53 (s, 1H), 8.26 (s, 1H), 8.38-8.47 (m, 2H), 8.72 (t, J=5.05 Hz, 1H), 11.56 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:35][CH2:36]O)[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:9]=2)=[O:7])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)[N:9]2[CH2:36][CH2:35][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6](=[O:7])[C:8]=12)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1CC1CC1
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacidcyclopropylmethyl-(2-hydroxyethyl)-amide (447) (80 mg, 0.159 mmol), in dichloromethane (5 mL), TPP (146.13 mg, 0.558 mmol) and diisopropyl azodicarboxylate (0.094 mL, 0.478 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate; Rf=0.2). After completion of the reaction, water (5 mL) was added and the mixture was extracted with dichloromethane (2×30 mL) and the organic phase was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200) column chromatography using 60-70% ethyl acetate in hexane as a gradient polarity mobile phase to get 9-benzyloxy-2-cyclopropylmethyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (448) (45.0 mg, 58%) as a white solid.
Reaction SMILES: N[C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].N(OC(C)(C)C)=O.[I:42]I>C(Cl)(Cl)Cl.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[I:42])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: II
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (582 mg, 1.16 mmol) in CHCl3 (35 mL) was added t-butyl nitrite (275 μL, 2.32 mmol). After 10 minutes, I2 (736 mg, 2.9 mmol) was added. The reaction was stirred at room temperature for 30 minutes, and then heated to 65° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (150 mL) and washed with aqueous NaHSO3, water, brine, saturated NaHCO3, and brine (50 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.30 (15% EtOAc/hexanes). LCMS=614.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.91 (m, 2H), 7.79 (s, 2H), 7.23 (m, 1H), 6.95 (m, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H), 4.07 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O.[NH2:21][CH2:22][C:23]([NH:25][CH:26]1[CH:31]2[CH:27]1[CH2:28][N:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30]2)=[O:24].C(OC(C(N)C(O)=O)=O)(C)(C)C.C(N1CC2C(C2N)C1)C1C=CC=CC=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:32]([N:29]1[CH2:28][CH:27]2[CH:31]([CH:26]2[NH:25][C:23]([CH2:22][NH:21][C:12](=[O:14])[CH2:11][CH:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:30]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Reactant: NCC(=O)NC1C2CN(Cc3ccccc3)CC21
Agent: CC(C)(C)OC(=O)C(N)C(=O)O
Agent: NC1C2CN(Cc3ccccc3)CC12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(C)cc1C(CC(=O)NCC(=O)NC1C2CN(Cc3ccccc3)CC21)c1ccccc1

Procedure:
The compound, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (209 mg, 0.77 mmole, 1 eq) and 2-amino-N-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-acetamide, 0.77 mmole, 1 eq (prepared by reacting t-butoxy carbonyl amino-acetic acid with 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett 1996, 1100) were dissolved in dimethylformamide (5 ml). The reaction mixture was cooled to 0° C. with subsequent addition of N-methyl morpholine (0.13 ml) and 1-hydroxy benzotriazole, HOBT (105 mg). The resulting mixture was diluted with water and extracted the organic compound with ethyl acetate. The solvent was removed under reduced pressure. The crude organic compound thus obtained was purified by column chromatography using 80% ethyl acetate in hexane. Yield=367 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Nc1ccc2c(c1)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3c(c2)CCC3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Aminoindane (266 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 270 mg of the nonpolar diastereoisomer of N′-indan-5-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid (m.p. 162-164° C.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH:18]([CH3:23])[C:19]2=O)=[CH:15][CH:14]=1.ClCCl.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.O>[CH2:31]([O:30][C:27](=[O:29])[CH2:28][C:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:21]=2)[CH2:17][C:18]=1[CH3:23])[CH3:32]
Reactant: CCOC(C)=O
Reactant: CC1Cc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1=C(C)Cc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 1 h

Procedure:
Triethylphosphonoacetate (22.41 g, 100 mmole) is added dropwise under nitrogen to a stirred and cooled (0° C.) slurry of Nail (57% in oil, 4.27 g, 100 mmole) in dry toluene (250 mL). The cooling bath is removed and stirring continued at room temperature for 60 minutes whereby an almost homogeneous solution is obtained. A solution of the indanone (15.15 g, 50 mmole) of Step E, in toluene (50 mL) is then added dropwise. The flask is placed in an oil bath heated at 95° C. for 19 hours (TLC, traces of starting material present, dichloromethane-ethyl acetate 9:1, UV, Vaughn's). The reddish solution is cooled, diluted with water and extracted with ethyl acetate (3 times). The combined extracts are washed with brine, dried (anhydrous K2CO3) and evaporated to dryness. The residue (heavy brown oil) is flash chromatographed (on silica Merck-60, eluted using a gradient dichloromethane AE dichloromethane:ethyl acetate 84:16) to provide the title compound as a mixture of endo and exo isomers (16.3 g, 87.4%, oil that solidifies upon standing) together with unreacted, more polar starting material (1.84 g, 12% recovery).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:17]C(=O)C)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]=[C:9]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]=2[CH:13]=1
Reactant: CC(=O)Nc1ccc2nc(-c3cc(C)c(=O)n(C)c3)n(Cc3ccccc3)c2c1
Agent: Cl
Product: Cc1cc(-c2nc3ccc(N)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
N-[3-Benzyl-2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3H-benzoimidazol-5-yl]-acetamide I-9″ (3.000 g; 7.763 mmol) is suspended in 8 N HCl (74 mmol). The reaction mixture is stirred for 3 h at 100° C. The reaction is cooled to RT and then quenched slowly with sodium bicarbonate (until reaching a basic pH). The reaction is extracted with MeOH/DCM. The combined organic layer is dried over Na2SO4 and concentrated in vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(#N)C.C(O)C>[CH3:25][O:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[CH2:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C:17]=2[CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)Cc2ccccc2)cc1

Procedure:
30g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine and 6,0 g of phenylacetic acid chloride are heated to the boil under reflux in 70 ml of acetonitrile for 7 hours. After working up in a manner analogous to that described in Example 31, and upon adding dilute hydrochloric acid in ethanol to the crude product, the dihydrochloride form of the title compound slowly crystallizes (melting point 240°-245°).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](B(O)O)=[CH:9]3)=[CH:4][C:3]1=2.[CH2:22]([N:25]1[CH:29]=[C:28](I)[CH:27]=[C:26]1[C:31]([O:33][CH3:34])=[O:32])[CH2:23][CH3:24]>>[CH2:22]([N:25]1[CH:29]=[C:28]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:12]4[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][C:2]([CH3:21])([CH3:1])[C:3]=4[CH:4]=3)[CH:9]=2)[CH:27]=[C:26]1[C:31]([O:33][CH3:34])=[O:32])[CH2:23][CH3:24]
Reactant: CCCn1cc(I)cc1C(=O)OC
Reactant: CC1(C)CCC(C)(C)c2cc3cc(B(O)O)ccc3cc21
Product: CCCn1cc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1C(=O)OC
Yield: 22.3 %

Procedure:
Following the basic procedure of Example 7(f), by reacting 1.7 g (6 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthrylboronic acid with 1.47 g (5 mmol) of methyl N-propyl-4-iodo-2-pyrrolecarboxylate, 450 mg (22%) of methyl N-propyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)-2-pyrrolecarboxylate were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[C:41]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[C:2]([C:48]3[CH:49]=[CH:50][C:45]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:46][CH:47]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Product: CC(C)(C)c1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 86.5 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic acid (125 mg, 0.69 mmol) by following general procedure D yielding the title compound (95 mg) as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccccn1
Product: c1ccc(CNc2nccc(-n3cnc4ccccc43)n2)nc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-(aminomethyl)pyridine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 303.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.63 (m, 2H); 8.46 (d, J=5.3 Hz, 1H); 8.12 (br s, 1H); 7.86 (m, 1H); 7.70 (m, 1H); 7.38 (m, 3H); 7.24 (m, 1H); 6.85 (d, J=5.3 Hz, 1H); 6.50 (br s, 1H); 4.87 (d, J=5.4 Hz, 2H).