Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[CH:3](OC)OC.[NH2:16][C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1>CC(C)=O>[Cl:23][C:22]1[C:17]2[N:18]([C:2]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=3)=[CH:3][N:16]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(OC)C(Br)c1ccnc(SC)n1
Solvent: CC(C)=O
Product: CSc1nccc(-c2cnc3c(Cl)nccn23)n1

Procedure:
Alternatively, intermediate 7 used in the synthesis of compounds of formula Ia can be prepared according to Schemes 2-4 below. 2-Methylsulfanyl-pyrimidine-4-carbaldehyde (8) can be condensed with (methoxymethyl)triphenylphosphonium chloride (Wittig reaction) to give 4-(2-methoxy-vinyl)-2-methylsulfanyl-pyrimidine (9). Oxidation of (9) with N-bromosuccinimide in methanol provides 4-(1-bromo-2,2-dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (10). Condensation of (10) with 2-amino-3-chloropyrazine (1) in aqueous acid and a co-solvent such as acetone gives 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (11). Compound 11 can then be reacted with an appropriate amine (HNR1R2) either in excess or in the presence of another base, such as diisopropyl ethyl amine, in an appropriate solvent, such as ethanol or butanol, between room temperature to reflux to give the intermediate 7. Intermediate 7 can also be prepared via the ethyl homologs 9′ and 10′ according to Scheme 4 below. Compound 9′ (the ethyl homolog) can be prepared by the reaction ethyl ethynyl ether (13) with borane—tetrahydrofuran complex followed by palladium catalyzed coupling with 4-chloro-2-(methylthio)pyrimidine (12). Oxidation of 9′ with N-bromosuccinimide in ethanol provides the ethyl homolog 10′. Homolog 10′ can be converted to intermediate 7 in the same way as 10.
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:48])[CH2:21][CH2:22][CH2:23][C:24]([CH3:47])([OH:46])[C:25](=[O:45])[CH2:26][CH2:27][C:28]1([O:44][CH2:43][CH2:42][O:41]1)[CH2:29][O:30][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[CH3:56][S:57]([CH3:59])=O>>[O:1]([CH2:19][CH:20]([CH3:48])[CH2:21][CH2:22][CH2:23][C:24]([CH3:47])([O:46][CH2:56][S:57][CH3:59])[C:25](=[O:45])[CH2:26][CH2:27][C:28]1([O:41][CH2:42][CH2:43][O:44]1)[CH2:29][O:30][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCC2(CCC(=O)C(C)(O)CCCC(C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCCO2)cc1
Solvent: CC(=O)OC(C)=O
Product: CSCOC(C)(CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CCC1(COS(=O)(=O)c2ccc(C)cc2)OCCO1
Reaction time: 20 h
Yield: 91 %

Procedure:
11-t-Butyldiphenylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-6-hydroxy-5-oxo-1-tosyloxyundecane (1.15 g) is dissolved in dimethyl sulfoxide (8.15 ml), acetic anhydride (8.15 ml) is added and the resulting solution is stirred for 20 hours. The solvents are removed in vacuo below 70° C. and the residue is partitioned between ether and saturated sodium bicarbonate solution. The organic layer is washed with brine and dried (sodium sulfate). The solution is removed in vacuo to give 11-t-butyldiphenylsiloxy-6,10-dimethyl-2,2-ethylenedioxy-6-methylthiomethoxy-5-oxo-1-tosyloxyundecane (1.13 g, 91%) as a yellow oil; nmr (CDCl3,δ) 0.88 (d, CH3CH), 1.04 [s, CH3)3 --C], 1.28 (s, ##STR39## 2.17 (s, SCH3), 2.42 (s, CH3 --Ph), 3.42 (d, OCH2CH), 3.89 (s, OCH2CH2O and TsOCH2C), 4.41 (s, OCH2S), 7.2--7.9 (aromatic H).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:5]([C:1]#[N:2])[CH:6]=[N:7][CH:8]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(C#N)c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
CuCN (5.22 g, 58.3 mmol) was added to a solution of methyl 5-bromonicotinate (6 g, 27.8 mmol) in dry DMF (150 mL). The solution was purged with argon and heated to 160° C. for 12 h under argon atmosphere. The reaction mixture was cooled to room temperature and then quenched with saturated NH4Cl solution. Further EtOAc was added and the reaction mixture was stirred for 10 min. The reaction mixture was filtered through a Celite plug, the organic layer was separated, washed with water and brine, and dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure to get methyl-5-cyano-nicotinate as greenish-white solid (2.7 g, yield 60%): 1H NMR (300 MHz, DMSO-d6) δ 9.29-9.27 (m, 2H), 8.77 (s, 1H), 3.91 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH-].[K+].CO.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][C:24]([C:33](=[O:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>CN(C)C=O>[C:33]([C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:26][CH2:25]1)(=[O:35])[CH3:34]
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCCl)CC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)C1(c2ccccc2)CCN(CCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 50 °C

Procedure:
1.65 Grams of 6-hydroxycarbostyril and 0.75 g of granular potassium hydroxide were mixed with 50 ml of methanol and concentrated under a reduced pressure to dryness. To the residue obtained was added 50 ml of dimethylformamide and mixed well, then 2.6 g of 1-(3-chloropropyl)-4-acetyl-4-phenylpiperidine was added and heated at 50° C. for 6 hours under stirring condition. The reaction mixture was concentrated under a reduced pressure to dryness and 20 ml of 5%-sodium hydrogencarbonate aqueous solution was added thereto and stirred. The insoluble matters were collected by filtration and washed with water. After dried the insoluble matters were recrystallized from ethanol to obtain 1.1 g of 6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]carbostyril as in the form of colorless prism-like crystals. Melting point: 192.5°-194° C.
Reaction SMILES: [CH2:1]([N:4]([C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=O)[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[NH2:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:38][CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:1]([N:4]([C:16]([CH3:21])([CH3:20])[C:17]([NH:22][C@@H:23]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[CH:49][CH:48]=1)[C:24]([N:26]([CH2:38][CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:19])[NH:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)CC(OCC)OCC
Yield: 128 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)-2-methylpropanoic acid (Compound VI-4) (317 mg, 1.1 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (502 mg, 0.73 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=97:3) to obtain the title compound (716 mg, 128%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>ClC1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
21.2 g of anhydrous aluminum chloride are introduced into 130 g of chlorobenzene and the mixture is cooled to 0° C. A solid mixture of 8.3 g of itaconic anhydride and 13.2 g of 4-chlorobiphenyl is added in portions in the course of one hour. The reaction mixture is stirred at 0° C. for three hours and then added to ice water. The solid reaction product is filtered off and washed twice with water (50 ml). The product is dried at room temperature and about 100 mbar until free of solvent and water. 4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is obtained in a yield of 75% as a colorless, finely crystalline powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:6]([N:10]=[CH:11][CH:12]=2)=[C:7](O)[N:8]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[CH3:1][S:2][C:3]1[NH:4][C:5]2[C:6]([N:10]=[CH:11][CH:12]=2)=[C:7]([Cl:26])[N:8]=1
Reactant: CSc1nc(O)c2nccc-2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CSc1nc(Cl)c2nccc-2[nH]1

Procedure:
Compound (3.2) (8.7 g, 48 mmol) was mixed with phosphorus oxychloride (350 ml) and N,N-diethylaniline (17.5 ml). This mixture was heated under reflux for 4 hrs; the brown solution was then concentrated under reduced pressure. The residual oil was treated with an ice-water mixture and stirred until the ice had melted. The resultant mixture was extracted repeatedly with ether until no more UV-active material was being extracted, the combined aqueous extracts were dried (MgSO4), filtered and evaporated to a light beige solid. Dried under vacuum at 50° C. to give (3.3), 7.3 g (76%). δH (300 MHz, DMSO-d6) 1.78 (3H, s, SCH3), 5.70 (1 H, d, J 3.7 Hz, H7) and 6.51 (1H, d, J 3.7 Hz, H8) ppm.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:4]#[N:5].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[OH:1][CH2:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:4]#[N:5]
Reactant: Cc1cccc(C)c1C(C#N)=CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C(C#N)CO
Reaction time: 2 h

Procedure:
58 g (0.33 mol) of hydroxymethylene-2,6-dimethylphenylacetonitrile are dissolved in 250 ml methanol and combined with 37 g (0.59 mol) of sodium cyanoborohydride. After 2 h, 250 ml of acetic acid are added dropwise, during which time the mixture heats up to 50° C. After the exothermic reaction has died down, the mixture is refluxed for a further 3 h. It is left to cool and the mixture is evaporated down in vacuo. The residue is mixed with 500 g of ice, neutralised with ammonia and extracted twice with 500 ml of ethyl acetate. The combined organic extracts are washed with 100 ml of water. After drying, the solvent is eliminated in vacuo. The residue is further processed from the crude state. 54.1 g (92% of theory) of the title compounds are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCCl)c2ccc(F)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 10.6 parts of N-(4-fluoro-phenyl)-4-methylbenzenesulfonamide in 68 parts of N,N-dimethylformamide were added portionwise 2.1 parts of a sodium hydride dispersion 50%: temp. roses to 35° C. After stirring for 20 minutes, the whole was cooled in an ice-bath (about 15° C.) and 12.6 parts of 1-bromo-3-chloropropane were added quickly. Stirring was continued first for 20 minutes at room temperature, then for 3 hours at 75° C. and further overnight at room temperature. The reaction mixture was poured onto ice-water and the prcduct was extracted with methylbenzene. The extract was washed three times with water, dried, filtered and evaporated. The residue was crystallized from petroleumether. The product was filtered off and recrystallized from 2,2'-oxybispropane, yielding 11.37 parts (83.2%) of -N-(3-chloropropyl)-N-(4-fluorophenyl)-4-methylbenzenesulfonamide (intermediate 83).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 2-(BOC)aminoethanol (3.2 g, 20.0 mmol) in DCM (60 mL) were added TEA (5.6 mL, 40.0 mL) and acetyl chloride (3.36 mL, 30 mmol) at 0° C. After the reaction solution was stirred for 2 h, the solvent was removed, and the residue dissolved in water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/10) to give the title compound (3.2 g, 80%).
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19](Cl)=[O:20]>C1C=CC=CC=1>[CH2:1]([NH:7][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([CH3:25])[CH:24]=[C:16]([CH3:15])[CH:17]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCC1CCCO1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C)cc(C(=O)NCC2CCCO2)c1
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A mixture was formed containing 3.0 grams (0.03 moles) of tetrahydrofurfurylamine, 4.5 ml. triethylamine in 100 ml. benzene. Then, 3.7 ml. (0.25 moles) of 3,5-dimethylbenzoylchloride was added. After standing for 1/2 hour, the mixture was washed with 100 ml. of water, 1 normal HCl (50 ml.), 50 ml. of saturated sodium bicarbonate dried over magnesium sulfate and evaporated in vacuo to yield 4.4 grams of product ND30 1.5366.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=CCCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.5 %

Procedure:
Methyl 5-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)-2-pentenoate (1.40 g, 4.22 mmol) and 5% palladium/carbon (wet.) (700 mg) were suspended in methanol (50 ml). Under stirring at room temperature, the resulting suspension was subjected to catalytic hydrogenation at normal pressure for 20 hours. The catalyst was filtered off and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 20 g), whereby from hexane/ethyl acetate (4/1) eluate fractions, the title compound (1.09 g, 78%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][CH:37]1[CH2:49]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:49][CH:37]2[CH2:38][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][CH2:41][N:36]2[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Product: O=C1OC2(CCN(C(=O)c3cn(CC4CN(Cc5ccccc5)CCN4Cc4ccccc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 1,4-dibenzyl-2-chloromethyl-piperazine described in Journal of Medicinal Chemistry 1999, 42(9), 1587-1603) gave the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 100.2 %

Procedure:
A solution of ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.40 g, 3.89 mmol) in a mixture of ethyl acetate (300 ml) and ethanol (75 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (200 mg) and under one atmosphere of hydrogen for four hours to give 1.05 g (100% yield) of the title compound as light yellow needles; mp 155-156° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 3.46 (2H, m, CH2), 3.75 (2H, t, J=8.3 Hz, CH2), 3.92 (2H, m, CH2), 4.20 (2H, t, J=8.3 Hz, CH2), 4.43 (2H, q, J=7.1 Hz, OCH2), 10.20 (1H, s, OH). Anal. Calcd for C11H15N3O5: C, 49.06; H, 5.61; N, 15.60. Found: C, 49.09, H, 5.73; N, 15.58.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:46]1([NH2:51])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:46]1([NH:51][C:40]([CH:37]2[CH2:38][CH2:39][N:34]([C:32]([N:12]3[C@@:13]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[C@@:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([CH3:16])[N:15]=[C:11]3[C:8]3[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=3[O:43][CH2:44][CH3:45])=[O:33])[CH2:35][CH2:36]2)=[O:41])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)NC2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid (example 211) was reacted with cyclopentylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H49Cl2N5O3 [(M+H)+] 718.3285, observed 718.3288.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][CH:19]([O:32][CH2:33][CH3:34])[CH2:20][CH2:21][CH2:22][NH:23]C(C1CCCCC1)=O)[CH3:17]>>[CH2:33]([O:32][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][NH:23][C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14])[CH3:34]
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Product: CCOC(CCCNC(=O)N1CCN(c2ccccc2)CC1)OCC

Procedure:
4-Phenylpiperazine-1-carboxylic acid (4,4-diethoxybutyl)amide (61B) is prepared from 61A as described for 20A. The product is obtained in almost quantitative yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH:27]1([CH2:26][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[N:23]([CH3:24])[CH3:25])[CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropanamide hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 372.2278 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([C:10]1[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].[N:16]([CH2:19][C:20]([CH3:28])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18]>>[ClH:1].[CH3:28][C:20](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)[N:18]=[N:17]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCCCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCCCc2c[nH]c(N)n2)nn1
Yield: 64.5 %

Procedure:
4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.098 g, 0.568 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.118 g, 0.681 mmol) following the general procedure for click reactions outlined above to produce 4-{6-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-hexyl}-1H-imidazol-2-ylamine hydrochloride (0.147 g, 85%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), δ 7.25-7.15 (m, 5H), δ 6.65 (s, 1H), δ 6.36 (s, 1H), δ 5.23 (s, 2H), δ 2.78 (t, 2H), δ 2.38 (t, 2H), δ 1.74 (s, 3H), δ 1.64 (m, 2H), δ 1.51 (m, 2H), δ 1.33 (m, 4H) ppm; 13C (75 MHz, CD3OD) δ 147.5, 136.3, 132.9, 132.8, 129.9, 128.9, 128.6, 128.5, 128.3, 127.7; HRMS (ESI) calcd for C21H29N6(M+) 365.2448. found 365.2448.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (3.2 g, 0.02 mol), 2,5-dichlorophenol (3.59 g, 0.022 mol), and potassium carbonate (3.0 g, 0.022 mol) in 25 ml of anhydrous DMF was heated to 150° C. with stirring overnight. After cooling to room temperature, the reaction mixture was poured into 500 ml of ice water and stirred for 30 min. The precipitates were collected by filtration, washed with water, and dried in vacuo to give 5.72 g (94.7%) of crude product.