Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)=O.[NH2:19][C:20]([NH2:22])=[S:21].[C:23]([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[NH2:19][C:20]1[S:21][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:23][N:22]=1
Reactant: NC(N)=S
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC=O
Product: CCOC(=O)c1cnc(N)s1
Temperature: 15 °C
Reaction time: 3 h
Yield: 137 %

Procedure:
To a -10° C. solution of potassium tert-butoxide (150 g, 1.3 mol) in THF (1.35 L) was added a solution of ethyl chloroacetate (139 mL, 1.3 mol) and ethyl formate (103 mL, 1.27 mol) in THF (150 mL) dropwise over 75 minutes, with good mechanical stirring. A THF rinse (25 mL) was added over 5 minutes. The thick solution was stirred another 3 hours at ca. -5° to 0° C., then the reaction was quenched by addition of a solution of NaCl (240 g) and conc. HCl (90 mL) in water (960 mL). The mixture was allowed to warm to 15° C. and the lower aqueous layer was discarded. Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution of chloroaldehyde. The solution was warmed to 65° C. and refluxed for 1 hour, then cooled to 30° C. Addition of a solution of K2CO3 (88 g, 0.64 mol) in 1500 mL water produced two layers (aqueous pH=7). The THF was removed under vacuum at ≤45° C., causing the product to precipitate as a yellow solid. The slurry was cooled to 15° C., and the product was collected on a fritted Buchner funnel and washed with 3×200 mL water, then dried 24 hours in a vacuum oven at 55° C. to provide 151 g of title compound as a yellow solid, m.p. 155°-158° C. 1H NMR (DMSO-d6) δ7.8 (br s, 2H, NH2), 7.62 (s, 1H), 4.13 (q, 2H), 1.18 (t, 3H). 13C NMR (DMSO-d6) δ173.4, 161.3,147.9, 114.5, 60.1, 14.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:19][C:20]([OH:22])=[O:21].Br>C(#N)C>[Br-:10].[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:19][C:20]([OH:22])=[O:21])=[CH:4]1)([OH:17])=[O:16]
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C(O)CBr
Reactant: O=C(O)CCCCBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCn1c[n+](CC(=O)O)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. 2-bromoacetic acid (2.15 g, 15.46 mmol) was added to the solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 3.11, 3.56, 4.68, 4.91, 5.24, 8.24, 10.06, 12.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[CH:7]2.[Li+].C[Si]([N-:18][Si](C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH2:18])[CH:8]=[CH:7]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Nc1ccc2cccc(Br)c2n1

Procedure:
Other cyclic amides of the present invention can be prepared such as the 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones 16 as described in Scheme 9. Substituted amines are coupled to the 8-bromo-2-chloroquinoline through treatment with base, such as LiHMDS, at a temperature of about RT, to afford the desired 8-bromoquinolin-2-amine 13. The bromo compound 13 is converted to the boronic acid 14 via treatment with a palladium catalyst, such as Pd(dppf)2Cl2, bis(pinacolato)diboron, and a base such as KOAc, at a temperature higher than RT, preferably above about 75° C., more preferably at about at 115° C. Coupling of the boronic acid 14 with the protected 7-bromo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 11 such as in the presence of a palladium catalyst, such as Pd2(dba)3 or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloro-palladium(H), and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine and a base such as K3PO4, at a temperature higher than RT, preferably above about 75° C., more preferably at about at 130° C., gave the protected 7-(quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 15. Deprotection, such as with acid, at a temperature higher than RT, preferably at about 50° C., affords the desired 7-(quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 16.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[CH2:18]([O:17][C:15]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:4][CH2:5][N:6]2[C:14]3[C:9]([CH:8]=[C:7]2[C:2]1=[O:1])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCn2c(cc3ccccc32)C1=O
Reaction time: 16 h
Yield: 65.9 %

Procedure:
A solution of 5 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate (prepared as described in Example 1) in 200 ml of dimethylformamide was treated with 550 mg of sodium hydride. The mixture was stirred under a nitrogen atmosphere and then a solution of 3.6 g of ethyl bromoacetate in 50 ml of dimethylformamide was added. After 16 hours, the mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with water, dried and concentrated to give 4.4 g of ethyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[Br:24]N1C(=O)CCC1=O.O.C(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:10]1[CH:11]=[C:12]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:13]([NH2:16])=[C:14]([Br:24])[CH:15]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(CC1CCC1)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)C(CC1CCC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a solution of the 2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was added N-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was stirred at 25° C. for 16 h and a mixture of water and methylene chloride (100 mL/100 mL) was added. The reaction mixture was extracted with methylene chloride (2×50 mL) and the organic phases were separated. The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography eluting with heptane-EtOAc (4:1) to give the product (13.9 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.06 (d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz, 2H), 4.21 (br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H), 2.20-1.89 (m, 4H), 1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 144.6, 134.4, 128.9, 125.7, 123.0 (d, 1JCF=277.6 Hz), 110.9, 108.7, 66.5 (q, 1JCF=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0, 18.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:3]=1.[H][H]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(Sc3ccncc3)c(F)c2)cc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cc(Nc3ccc(Sc4ccncc4)c(F)c3)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
A dry flask under argon was charged with 10% palladium on carbon (20 mg). A solution of N-[2-amino-6-(3-nitrophenyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine (Example 20, 200 mg, 0.46 mmol) in ethanol (12 mL) and EtOAc (1 mL) was added via syringe through a septa to the palladium on carbon. The flask was then fitted with a hydrogen balloon and stirred at room temperature for 48 h. At this time the palladium was filtered through a pad of Celite®. The filtrate was coated on silica and purified on the MPLC (Biotage) with 2-8% MeOH in CH2Cl2 to afford the desired product as a solid (120 mg, 64%). TLC (6% MeOH in CH2Cl2) Rf0.26; MS (ES) 405 [M+H]+; 1H-NMR (DMSO-d6) δ 5.22 (bs, 2H), 6.45 (s, 1H), 6.49 (bs, 2H) 6.62-6.65 (m, 1H), 6.98 (d, J=6.4 Hz, 2H), 7.02-7.16 (m, 3H), 7.43-7.55 (m, 2H), 8.30-8.35 (m, 3H), 9.75 (bs, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.[C:18]([O:22][C:23](NC(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To an ice-cooled solution of 2.9 g of 8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of tetrahydrofuran there was added 3.3 g of 2-(tertbutoxycarbonyl-amino)-2-phenylacetonitrile and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography using 50 g of silica gel. The column was eluted with chloroform, chloroform containing methanol and 4.1 g of the titled compound was obtained from a eluate when the eluant was chloroform containing 1% (v/v) of methanol.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]([OH:20])=O)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[NH2:32][C:33]1[C:41]([CH3:42])=[CH:40][C:39]([I:43])=[CH:38][C:34]=1[C:35](O)=[O:36]>C(#N)C>[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]3[O:20][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([I:43])[CH:40]=[C:41]([CH3:42])[C:33]=4[N:32]=3)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) in acetonitrile (50 mL) was added dropwise a mixture of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step C) (10.0 g, 34.31 mmol) and triethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at −5° C. The reaction temperature was then maintained at 0° C. throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Step A) (9.51 g, 34.31 mmol) was added and stirring was continued for an additional 10 minutes. A solution of triethylamine (9.56 mL, 68.62 mmol) in acetonitrile (15 mL) was then added dropwise, and the reaction mixture was stirred 30 minutes, followed by the addition of methanesulfonyl chloride (2.91 mL, 37.74 mmol). The reaction mixture was then warmed to room temperature and stirred 2 hours. The solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 8.53 g of the title compound as a yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].NCCC(O)=O>C(O)CCC>[N+:14]([C:17]([CH3:18])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([O-:16])=[O:15]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC[N+](=O)[O-]
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Yield: 20.2 %

Procedure:
A mixture of 292 g (1.70 mole) of 4-(1H-imidazol-1-yl)benzaldehyde, 153.7 g (1.97 mole) of nitroethane (96%), and 15.4 g (.173 mole) of β-alanine in 1000 ml n-butanol is refluxed for nine hours. The reaction mixture is allowed to cool overnight, the solid collected, and washed successively with ether and water to give 78.7 g of dark yellow crystals, mp 119°-120° C. Concentration of the filtrate to approximately 500 ml and cooling at 0° gave a second crop (87.2 g) of the product, mp 116°-118° C.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[C:32]1([N:38]2[CH:42]=[C:41]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:40](=[O:49])[NH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O:50]1CCC[CH2:51]1>>[O:49]=[C:40]1[C:41]([CH:43]2[CH2:44][CH2:45][N:46]([C:51]([NH:1][C@@H:2]3[N:8]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:6]4[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=4[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]3=[O:24])=[O:50])[CH2:47][CH2:48]2)=[CH:42][N:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:39]1
Reactant: C1CCOC1
Reactant: O=c1[nH]n(-c2ccccc2)cc1C1CCNCC1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(c2cn(-c3ccccc3)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (137 mg, 0.411 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (0.057 mL, 0.411 mmol) were added to a solution of p-nitrophenylchloroformate (83 mg, 0.411 mmol) in tetrahydrofuran (20 mL) at 0° C. After 1 h, 1-phenyl-4-piperidin-4-yl-1,2-dihydro-3H-pyrazol-3-one (50 mg, 0.205 mmol) and additional triethylamine (0.171 mL, 1.23 mmol) were added and the reaction warmed to ambient temperature and was then heated at 50° C. After 4 h, the reaction was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organics were washed with water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane→10% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (27 mg). MS 603.23 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:25][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc2ccccc12
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2ccccc12

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 1-naphthaleneamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [H][H].[N:3]1([CH2:12][CH2:13][CH2:14][NH2:15])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Pd].C(O)C>[CH2:16]([NH:15][CH2:14][CH2:13][CH2:12][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: [H][H]
Reactant: NCCCn1cnc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CNCCCn2cnc3ccccc32)cc1

Procedure:
0.5 Gram of 10% palladium on charcoal was prehydrogenated in 100 ml. of absolute ethanol until the uptake of hydrogen stopped. Then, a solution of 10 grams of 1H-benzimidazole-1-propanamine and 6.7 grams of benzaldehyde in 50 ml. of absolute ethanol was added and the mixture was stirred at atmospheric pressure and room temperature under hydrogen until the calculated amount of hydrogen was taken up. The catalyst was then removed by filtration and the solvent was evaporated to leave N-benzyl-1H-benzimidazole-1-propanamine as a colorless oil. This material was sufficiently pure for further reaction but, if desired, a pure sample could be obtained by column chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl.[Si](C=[N+]=[N-])(C)(C)C.CCCCCC.[CH3:28]O>C1COCC1>[CH3:28][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:2]=1[Br:1]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: [OH-]
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
The mixture of 2-bromo-4-methyl-benzoic acid (9.5 g, 32.3 mmol), THF (30.0 mL), and 5.0 M NaOH (26 mL, 129 mmol) is stirred at room temperature overnight. The mixture is acidified with 5.0 M HCl and is extracted with EtOAc (80 mL). The organic phase is washed with brine (60 mL) and is dried (Na2SO4). After filtration, the filtrate is concentrated under reduced pressure to a residue. The residue is dissolved in CH2Cl2 (50 mL) and MeOH (50 mL) and is treated with 2.0 M TMSCHN2 in hexane (30 mL, 60 mmol) at 0° C. for 1.0 h. The reaction mixture is concentrated to a residue and the residue is purified by flash chromatography to afford the title compound as a solid (2.3 g, 29%). LC-ES/MS m/e 247.0 (M+1).
Reaction SMILES: [BrH:1].[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1>CS(C)=O>[Br-:1].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: Br
Reactant: N=C(C1CC1)C1CC1
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Product: [Br-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of dicyclopropylmethanimine hydrobromide (1.00 g, 5.26 mmol) in 6.0 ml of dimethyl sulfoxide was heated with stirring at 100° C. for 1 hour. The solvent was distilled out in vacuo and of isobutyl alcohol (8 ml) was added to the residue. Precipitated crystals was obtained and dried in vacuo to afford 0.56 g (Yield: 56%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].C[Li].C([Li])(C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1.C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[SH:9])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(S)c(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-fluoro-thiophenol (6.0 g, 28.9 mmol) in dry tetrahydrofuran (TBF, 25 mL) at −78° C. was slowly added methyl lithium (1M in cumene/TBF, 28.9 mL, 28.9 mmol). After 30 min at −78° C., tert-butyl lithium (1.7 M in THF, 39.9 mL, 63.8 mmol) was added and the reaction mixture was stirred 30 min at −78° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.77 g, 28.9 mmol) in THE (20 mL) was added and the reaction mixture was allowed to warm to rt and stirred overnight. Water (50 mL) and ethyl acetate (25 mL) were added, and organic phase was discarded. The aqueous phase was extracted with ethyl acetate (50 mL) and saturated aqueous ammonium chloride (25 mL). The organic phase was washed with saturated aqueous ammonium chloride (25 mL) and dried over magnesium sulfate, and evaporated to afford the crude product. The crude product was purified by flash chromatography on silica gel (eluent: An increasing amount (0-20%) of ethyl acetate in heptane). Yield: 4.67 g (49%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12]3[C:17]([NH:18][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[NH:19]1C2C(=CC=CC=2)[C:22](=[O:23])[C:20]1=O.NCCO.CO>C(OCCO)C>[ClH:1].[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=1[C:2]([NH:19][CH2:20][CH2:22][OH:23])=[N:3]2
Reactant: Clc1nc2ccccc2c2[nH]c3ccccc3c12
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CO
Solvent: CCOCCO
Solvent: NCCO
Product: Cl
Product: OCCNc1nc2ccccc2c2[nH]c3ccccc3c12
Yield: 61 %

Procedure:
A mixture of compound 4a as obtained from the above Synthesis Ex. 1 (0.50 g, 2 mmol) and 2-aminoethanol (0.24 g, 4 mmol) in 2-ethoxyethanol (20 mL) was heated at 140-150° C. for 48 hrs (by TLC monitoring). After cooling, the reaction mixture was evaporated in vacuo to give a residue, which was treated with MeOH (30 mL) to result in precipitation. The resultant precipitate was collected by filtration and recrystallized with MeOH to give the title compound 7d as a white powder (0.38 g, 61% yield).