Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[CH3:45][Si:46]([CH3:77])([C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[O:47][C:48]1[CH:55]=[C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:62][C:63]=2[CH3:64])[CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([O:16][CH3:17])[C@@H:50]([C:49]1[CH:52]=[CH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[O:62][C:63]=2[CH3:64])=[CH:55][C:48]=1[O:47][Si:46]([CH3:77])([CH3:45])[C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[OH:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C(C)C)c1
Reactant: COCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1.8 g (7.21 mmol) (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D. Hunziker, N. Wu, K. Kenoshita, D. E. Cane, C. Khosla, Tetrahedron Lett. 1999, 40, 635-638) were dissolved under an argon atmosphere in 10 ml CH2Cl2 and treated with 1.44 ml (8.42 mmol) Hünig's base. After cooling to −78° C., nBu2BOTf was added slowly (7.21 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 0.25 hours at −78° C. and for 1 hour at 0° C. After recooling to −78° C., a solution of 2.8 g (6 mmol) of 2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 10 ml CH2Cl2 was added via dropping funnel during 90 minutes and the mixture kept for 95 minutes at −78° C. and for one hour at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine and water, drying over magnesium sulfate, and evaporation of the solvents, followed by chromatography (silica gel, heptane/AcOEt) left finally 2.905 g (67%) of the title compound as a yellow oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].Cl>C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCNC(=O)c1ccc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylic acid (100 mg), EDC (47 mg) and HOBt (28 mg) in DCM (4 mL) was added octylamine (0.041 mL). The resulting reaction mixture was stirred for 3 h. DCM (15 mL) and an aqueous solution of HCl (1N, 10 mL) was added. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (15 mL) and dried over MgSO4. Evaporation of the solvents gave an oil which was purified by flash chromatography over silica gel (c-Hex/AcOEt 2/1) to give the title compound as a colorless oil (41 mg, 33%). M+(LC/MS(ESI)): 597.8; M−(LC/MS(ESI)): 595.0. HPLC (Condition A), Rt: 6.61 min (HPLC purity: 99.87%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])#[CH:25]>O1CCCC1.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>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15])(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)S(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(C#Cc2cccc(N)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
4-Bromo-1-(isopropylsulfonyl)-2-nitrobenzene (390 mg, 1.3 mmol), bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.08 mmol) and copper(I) iodide (20 mg, 0.1 mmol) were stirred in tetrahydrofuran (5 mL) with triethylamine (250 μL, 1.8 mmol). 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was stirred at rt for 1.5 hours. The mixture was evaporated, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound (250 mg, 60%). LCMS for C17H17N2O4S (M+H)+: m/z=345.1.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23](O)=[O:24])[CH2:4][CH2:3][CH2:2]1.[CH:29]([N:32](CC)C(C)C)(C)[CH3:30].C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>CN1CCCC1=O.CC#N>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:19]([CH3:22])=[N:20][N:21]=4)[C:13]=3[CH:12]=[C:11]2[C:23]([NH:32][CH2:29][CH3:30])=[O:24])[CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(CN4CCC4)c3)n12
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CN2CCC2)c1

Procedure:
To a solution of 6-[3-(azetidin-1-ylmethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.017 g, 0.045 mmol, from Step 7) in N-methylpyrrolidinone (1 mL) was added N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) and ethylamine (0.010 g, 0.018 mmol, Aldrich), followed by the addition of HATU (0.022 g, 0.059 mmol). When the reaction was complete as determined by LCMS, the reaction was diluted with MeCN, and TFA was added to aid in solubility. The product was purified via preparative HPLC-MS (Waters SunFire C18, 5 μm 30×100 mm, (H2O, 0.1% TFA) MeOH, flow rate: 60 mL/min). Yield: (10 mg, 35%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][CH2:26][C@H:13]4[C:12]=23)[N:4]=1.N12CCCN=C1CC[CH2:30][CH2:29][CH2:28]2.[CH2:38](Br)[CH:39]=[CH2:40]>CN(C)C=O>[CH2:30]([N:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][CH2:26][C@H:13]4[C:12]=23)[N:4]=1)[CH2:40][CH:39]=[CH2:38])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: C1CCC2=NCCCN2CC1
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 49.3 %

Procedure:
3.0 g (8.1 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, 20 ml of N,N-dimethylformamide, 3 ml (20 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5-5) and 6.54 g (54 mmol) of allyl bromide were stirred at 40° overnight. The reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution was washed with water. After drying the product was purified by chromatography on silica gel while eluting with melthylene chloride/methanol 19/1. There were obtained 1.8 g (49%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one, which was converted into the hydrochloride.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][NH:30][C:31]([C:33]1[N:34]2[CH:40]=[N:39][CH:38]=[C:35]2[S:36][CH:37]=1)=[O:32]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([C:31](=[O:32])[NH:30][CH2:29][CH2:28][OH:27])[N+:34]4=[CH:40]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: O=C(NCCO)c1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(=O)NCCO)[n+]4c3)[C@H](C)[C@H]12
Yield: 13.6 %

Procedure:
The same procedure as in Example 1 was repeated except that 93 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 80 mg of 3-(N-2-hydroxyethyl)carbamoylimidazo[5,1-b]thiazole were used, thereby obtaining 15 mg of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)=[O:18])[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OC1CCNCC1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)CC2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 4-piperidinol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=436.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:30][C@H:31]([CH2:39][OH:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[C:33]1([CH2:32][CH:31]([NH:30][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[N:22][C:14]=2[N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:39][OH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCCCOC(=O)N1CCN(c2ncccc2C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(c2ncccc2C(=O)NC(CO)Cc2ccccc2)CC1

Procedure:
13 g of 2-(4-butoxycarbonylpiperazin-1-yl)nicotinic acid were dissolved in 150 ml of methylene chloride and 14.7 ml of triethylamine analogously to Example 1c and treated successively with 6.4 g of phenylalaninol, 1.9 g of HOBT and 8.11 g of EDC, 16.7 g (90%) of the product being obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=O)[CH:18]=[CH:19][NH:20]2)=[CH:15][C:14]=1[C:24]([O:26]C1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[N:34]([CH3:37])C=O>>[CH3:37][NH:34][C:24]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:20]=[CH:19][CH:18]=[C:17]2[Cl:3])=[O:26]
Reactant: O=C(Oc1ccccc1)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CN(C)C=O
Product: CNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Yield: 89.7 %

Procedure:
After adding thionyl chloride (12 ml) and a catalytic amount of dimethylformamide to phenyl 7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (1.20 g, 3.23 mmol), the mixture was heated to reflux for 2 hours while stirring. The reaction solution was concentrated under reduced pressure and azeotropically distilled twice with toluene, the residue was suspended in dimethylformamide (20 ml), a 40% methylamine-methanol solution (5 ml) was gradually added while cooling in an ice water bath, and the mixture was stirred for 1 hour. The reaction solution was distributed between ethyl acetate-tetrahydrofuran (1:1) and water, and the organic layer was washed with saturated aqueous ammonium chloride solution, water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, diethyl ether and then hexane were added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (947 mg, 2.90 mmol, 89.7%) as light yellow crystals.
Reaction SMILES: C1C[CH2:10][N:9]2[C:4](=NCC[CH2:8]2)[CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[N:17][NH:18][CH:19]=1)([O-:14])=[O:13].C1C[O:23]CC1>>[CH3:8][N:9]([CH3:10])[CH2:4][CH:3]([OH:23])[CH2:2][N:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:19]=[N:18]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: C1CCOC1
Product: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(dimethylamino)propane-1,2-diol (934 mg, 7.84 mmol) in CH2Cl2 (8 mL) were added Bu2SnO (42 mg, 0.16 mmol), tosyl chloride (1.49 g, 7.84 mmol), and Et3N (1.10 mL, 7.92 mmol). The reaction mixture was stirred at rt for 2 hrs. The mixture was quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layers were dried over MgSO4 and concentrated to afford 3-dimethylamino-2-hydroxypropyl 4-methylbenzenesulfonate; [m/z (APCI+) 274.10 (M+H)+]. The residue was dissolved in THF (10 mL), then DBU (2.56 mL, 16.6 mmol) and 4-nitro-1H-pyrazole (602 mg, 5.32 mmol) were added and the resulting mixture was stirred at rt for 30 min. The mixture was then quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layer were dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (526 mg, 46° A yield) which was used without purification. m/z (APCI+) for C8H14N4O3 215.10 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([OH:25])=O)[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>C1COCC1.O>[CH2:30]([NH:37][C:23](=[O:25])[CH2:22][CH:21]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:29])[CH2:26][CH2:27][CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CC(=O)NCc1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To the suspension of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (20 mg, 0.049 mmol) in THF (1.0 mL) at room temperature are added benzyl amine (0.027 mL, 0.245 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol). Then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (40 mg, 0.21 mmol) is added and the reaction mixture is stirred for 16 hr. Water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. The crude is filtered through a short path of silica gel eluting first with CH2Cl2 then with 50% EtOAc in hexanes to give 23 mg (95%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid benzylamide. LCMS (ESMS): m/z 498.22 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCN(CCCN)CC1
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of N-[3-(4-ethoxycarbonyl-1-piperazinyl)propyl]phthalimide (28.9 g) in ethanol (300 ml) was added 100% hydrazine hydrate (8.4 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and evaporated. Under reduced pressure. After the addition of an aqueous solution of sodium hydroxide to the residue, the mixture was extracted with chloroform The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give an oil of 3-(4-ethoxycarbonyl-1-piperazinyl)propylamine (10.9 g).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C@@H:13]([OH:15])[CH3:14].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][C@@H:13]1[O:15][S:1](=[O:2])[N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)[CH2:12]1
Reactant: C[C@H](O)CNc1ccccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccccn2)S(=O)O1
Yield: 115.9 %

Procedure:
Thionyl chloride (8.8 ml, 14.35 g 0.12M) in dichloromethane (20 ml) was added dropwise to a cooled stirred solution of (S)-N-(2-pyridinyl)-1-amino-2-propanol (18.28 g, 0.12M) in dichloromethane (180 ml) and diisopropylethylamine (31 g, 0.24M) keeping the temperature below 5° C. After stirring at 0° for 1 h a solution of saturated sodium bicarbonate solution was added keeping the temperature below 5° C. The organic layer was separated, dried (Na2SO4) and concentrated to give 27.6 g of a yellow oil. The oil was chromatographed on silica using 40% ethyl acetate in hexane to give 20.28 g of a yellow oil containing a 4:3 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH3:16][NH2:17]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g, 39.1 mmol) in THF (100 mL) was cooled to −40° C. before being treated with a solution of methylamine hydrochloride (2.64 g, 39.1 mmol) in 10 ml of water followed by TEA (5.44 mL, 39.1 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 1 hour before being partitioned between 350 mL EtOAc and 30 mL brine. The organic layer was washed twice with brine, dried over MgSO4 and subjected to flash chromatography (330 g silica gel, 0-40% EtOAc/hexane) to afford 4-chloro-N-methyl-3-nitrobenzenesulfonamide (6.38 g, 65%) as a light yellow solid. MS (m/z) 251.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[N:11]=[CH:10]N[C:7]=2[CH:8]=1.[C:12](O)(=O)C>[Pd]>[CH3:1][O:2][CH:3]1[CH2:4][N:5]2[CH:12]=[CH:10][N:11]=[C:6]2[CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: COc1cnc2nc[nH]c2c1
Agent: [Pd]
Product: COC1CCc2nccn2C1
Yield: 97 %

Procedure:
Add acetic acid (40 mL) to a heterogeneous solution of 6-methoxyimidazopyridine (1.0 g; 1.0 equiv; 6.75 mmoles) and 10% palladium on carbon (1.0 g; 1.4 equiv; 9.40 mmoles). Evacuate and backfill the reaction vessel with nitrogen (3×) then hydrogen (3×). Vigorously stir the reaction under hydrogen at ambient temperature for 3 hours. Filter the reaction mixture through celite, and wash the filter cake with a 1:1 mixture of dichloromethane and methanol. Concentrate the filtrate and dissolve the crude product mixture in 20 mL methanol, then load onto a scx ion-exchange column. Elute with methanol followed by 2M ammonia in methanol to give 6-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.00 g; 97%) as a colorless oil. 1H NMR (DMSO): δ 1.84-1.94 (m, 1H), 2.00-2.09 (m, 1H), 2.63-2.68 (m, 2H), 3.27 (s, 3H), 3.77-3.82 (m, 1H), 3.92-4.03 (m, 2 H), 6.74 (d, 1H), 6.91 (d, 1H).
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([N:7]1[C@@H:16]2[C@@H:11]([C:12]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[CH:17][C:13]=3[CH2:14][CH2:15]2)[CH2:10][CH2:9][CH2:8]1)=O>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:12]3[C@@H:11]4[C@H:16]([CH2:15][CH2:14][C:13]=3[CH:17]=2)[NH:7][CH2:8][CH2:9][CH2:10]4)=[CH:27][CH:26]=1
Reactant: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
1 M aqueous NaOH solution (10 mL) is added to a solution of cis-2,2,2-trifluoro-1-[8-(4-methoxy-phenoxy)-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl]ethanone (0.95 g) in tetrahydrofuran (10 mL) at room temperature. The resulting solution is stirred at 35° C. overnight and then cooled to room temperature. The solution is extracted with ethyl acetate, the combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 95:5→70:30) to give the title compound as a colorless resin-like solid. Yield: 0.64 g (88% of theory); LC (method 1): tR=2.75 min; Mass spectrum (ESI+): m/z=310 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.[NH2-:13].[Na+].C(OCC)(=O)C.[BrH:21]>C1(C)C(C)=CC=CC=1>[BrH:21].[NH2:13][C:8]1[C:9]2[C:4](=[C:3]([OH:2])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COc1cccc2cnccc12
Reactant: [NH2-]
Agent: Br
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Nc1nccc2c(O)cccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
900 mg (5.66 mmol) of 5-methoxyisoquinoline was dissolved in 20 ml of xylene. 4.26 ml (28.3 mmol) of N,N,N′,N′-tetramethylenediamine and 1.17 g (30.0 mmol) of sodium amide were added to the obtained solution, and they were stirred at 140° C. for 1 hour. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, 10 ml of hydrobromic acid was added to the obtained crude product and they were heated under reflux for 6 hours. The solvent was evaporated to obtain the title compound.