Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:21]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and acetic anhydride (4 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 8 mg (60%) of N-acetyl-N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (the compound of formula (Igg)): 1H NMR (CDCl3) δ 8.48 (s, 1), 8.08 (d, 1), 7.76 (s, 1), 7.09 (s, 1), 6.66 (m, 3), 6.33 (m, 1), 5.94 (s, 1), 5.91 (s, 1), 4.43 (m,3), 3.40 (m, 2), 2.11 (d, 3), 1.14 (m); MS: 450.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.I[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17].O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC1CCCC1CI
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCCC1CNc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
4-Aminobenzonitrile (11.8 g.) and 1-iodomethyl-2-methylcyclopentane (16.3 g.) are dissolved in hexamethylphosphoramide (100 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (100 ml.) is added gradually. The mixture is then chilled in an ice bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. Recrystallization from ether-hexane affords 4-(2-methylcyclopentylmethylamino)benzonitrile as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1ncc(N)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1ncc(NC(=O)c2ccccc2Cl)s1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a mixture of 5-amino-2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole (66, 8.1 mg, 0.03 mmol) in 1 ml DCM were added 2-chlorobenzoyl chloride (3.8 μl, 2 eq), DIEA (52 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for 2 h, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.06 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to prep HPLC purification to give 3.7 mg of (2-chlorophenyl)-N-{2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-5-yl)}carboxamide (67) as yellow solid (yield: 31.9%; purity>90%). LC-MS: calcd. for C15H10ClF3N4OS: 387 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([O:15][P:16]([C:21]([NH2:24])([CH3:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(#N)C>[CH2:18]([O:17][P:16]([C:21]([NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:22])[CH3:23])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)C(C)(C)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
83 g of 3-nitrobenzoyl chloride in 150 ml of acetonitrile are added dropwise to a solution of 105 g of 2-aminopropane-2-phosphonic acid diethyl ester and 45 g of triethylamine in 300 ml of acetonitrile at 0° C., with good stirring. After completion of the addition, the mixture is stirred for a further 3 hours at 0° C.; it is then filtered and the solvent is distilled off in vacuo. The residue is purified by extraction by shaking with ether and aqueous 2 normal sodium carbonate solution. 99 g of 2-(3'-nitrobenzamido)propane-2-phosphonic acid diethyl ester of melting point 95°-96° C. are obtained. This product is reduced with hydrogen as indicated in Example 2.
Reaction SMILES: [CH:1]1([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>>[CH:1]1([N:7]=[C:8]([Cl:19])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: ClC(=NC1CCCCC1)c1ccc(Cl)cc1
Reaction time: 1.75 h

Procedure:
N-Cyclohexyl 4-chlorobenzamide (12.8 g, 53.9 mmole) and thionyl chloride (43.14 g, 363 mmole) were heated at reflux with stirring for 1.75 hours. Excess thionyl chloride was removed by distillation. The title compound was isolated by distillation (b.p. 130° C. at ~15 mm Hg) to yield 7.4 g (54%) of a clear colorless liquid which crystallized upon cooling.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=O)C.[OH-].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:11]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)OCCCCCC1CCCNC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-(3-piperidinyl)-1-pentanol acetate (7.37 g, 31.9 mmol) in THF (50 ml) was added a solution of potassium hydroxide (5.36 g, 96 mmol) in water (30 ml) and the mixture was stirred in an ice-water bath. To this was added a solution of benzyl chloroformate (5.00 ml, 35.0 mmol) in THF (25 mL) dropwise over a period of 40 mins. After stirring in the cold bath for 30 mins., the mixture was allowed to warm to rt and stirred for 5 hours. The organic solvent was removed by evaporation in vacuo and the aqueous phase was diluted further with water (75 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts was washed with saturated NaCl solution (100 ml), separated, dried (Na2SO4), filtered the solvent evaporated in vacuo and the residue was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 2×100 g cartridges using a gradient of 0-100% ethyl acetate in cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (6.50 g).
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=O)([O:13][CH3:14])[O:11]C>S1(CCCC1)(=O)=O.[Cl-].[Li+]>[C:10]([O:13][CH3:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)OC
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Yield: 70.1 %

Procedure:
The following example illustrates the use of alkali halide catalysts. A mixture of benzoyl chloride (7.03 g, 0.05 mole), dimethyl carbonate (4.5 g, 0.05 mole) and lithium chloride (0.106 g, 0.0025 mole) in 25 ml of sulfolane was heated to 150° C. for 22 hours. Distillation of the reaction mixture gave 4.77 g (70 percent yield) methyl benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:45][CH2:44][C:43]2([CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:47]2[CH2:48][CH2:49][C:43]3([CH2:44][CH2:45][N:41]([CH3:40])[CH2:42]3)[CH2:46]2)[N:8]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: CN1CCC2(CCNC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNc2nc(N3CCC4(CCN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 4 %

Procedure:
In DCM (30 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (429 mg, 0.96 mmol) and DIEA (0.22 mL, 1.12 mmol). 2-Methyl-2,7-diazaspiro[4.4]nonane (154 mg, 1.1 mmol) was then added. The reaction was conducted at ambient temperature overnight. The solvent was removed by rotary evaporation, followed by addition of water and extraction with ethyl acetate. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1) to give a white solid (20 mg, 4% yield).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>C1COCC1>[CH3:27][O:28][CH2:29][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: COCCl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.0 g, 4.07 mmol) in THF (20 mL) at −78° C. under nitrogen was added dropwise LDA (1.5 M in THF, 4.0 mL, 6.10 mmol). This solution was stirred for 1 hour at −78° C., after which methoxymethyl chloride (0.8 mL, 10.5 mmol) was added. The system was allowed to warm slowly to room temperature over 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (3×50 mL). The organic layer was dried over a pad of silica gel, and the solvent removed under vacuum. The title compound was isolated by silica gel chromatography (5-10% ethyl acetate:hexanes) as a clear oil (830 mg, 69% yield). MS (ES+) [M+H]+=302.4.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23](F)([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:22][CH:23]([F:32])[O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:3]3[CH2:11][CH2:10][N:9]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 mL microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.052 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[ClH:13].Cl.[CH2:15]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[CH2:15]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: COc1ccc(C(=O)CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(CC(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of 2-chloro-1-(4-methoxyphenyl)ethanone (3 mmol), N-phenacyl piperazine dihydrochloride (3 mmol) and K2CO3 (10 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-9), 0.68 g (62%), mp 226-228° C., M+ 352.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:6]2
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)CC(CN)CO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC1COc2ccc(OC)cc2C1
Reaction time: 1 h

Procedure:
A solution of 0.4 g (2.06 mmol) of the amine obtained in Step B in 20 ml of anhydrous dichloromethane is cooled to 0° C. 1 ml (7.2 mmol) of triethylamine and also 0.38 g (3.6 mmol) of butyryl chloride are added in succession to the medium. After one hour of stirring under argon, the reaction mixture is acidified with a 1N hydrochloric acid solution; the aqueous phase is then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title amide is obtained pure in the form of a white solid after passage over a silica column (eluant: petroleum ether/ethyl acetate 50/50).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[CH3:30]O>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:30])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CO
Agent: Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 92 %

Procedure:
100 g of deoxycholic acid was dissolved in 300 ml of methanol, and then 2 ml of hydrochloric acid was added thereto. The resulting mixture was refluxed for 1 hour. The methanol was distilled off. After the resulting mixture was dissolved in 400 ml of ethylether, it was washed with distilled water, sodium bicarbonate and brine several times. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to prepare 95 g (yield: 92%) of methyl deoxycholate represented by the following formula:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.C1C[O:20][CH2:19]C1>CCCCCC>[F:1][C:2]1[C:3]([CH:19]=[O:20])=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(F)cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1ccc(F)c(C=O)c1OC
Reaction time: 3 h

Procedure:
To a solution of 4-fluoro-1,2-dimethoxy-benzene (20.0 g, 128.07 mmol) in anhydrous THF (200 mL) under nitrogen at −78° C. was added dropwise a 2.5M solution in hexane of n-BuLi (102.4 mL, 256.14 mmol) for duration 30 min and the reaction mixture was further stirred at the same temperature for 3 h. The reaction mixture was quenched carefully with DMF (100 mL) at −65° C. to −40° C. and left overnight. 2N HCl (300 mL) was added dropwise at −60° C. and the mixture stirred for 30 min. The two layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification was completed by flash column chromatography (20% EtOAc/hexane). Yield 18.0 g (85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.39 (s, 1H), 7.09 (dd, J=9.4, 5.1 Hz, 1H), 6.84 (t, J=9.6 Hz, 1H), 3.98 (s, 3H), 3.88 (s, 3H). 19F NMR (376 MHz, CHLOROFORM-d): −126 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and methoxyacetyl chloride. m.p.: 155-157° C.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3].[CH:15](OCC)=[O:16]>>[NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][CH:15]=[O:16])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3]
Reactant: CCOC=O
Reactant: CC(N)Cc1cccc(NC(N)=O)c1
Product: CC(Cc1cccc(NC(N)=O)c1)NC=O

Procedure:
A mixture consisting of 4.8 gm of 1-(3'-ureido-phenyl)-2-amino-propane and 5 ml of ethyl formate was refluxed for five hours. Thereafter, the reaction solution was evaporated, and the residue was purified by chromatography on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethanol and ether, yielding the compound of the formula ##STR23## which had a melting point of 133°-136° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][Si:7]([CH3:22])([CH3:21])[O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][C:3]([N:12]1[CH2:13][C@H:9]([O:8][Si:7]([CH3:21])([CH3:22])[CH3:6])[CH2:10][C@H:11]1[C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4]
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CCl
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A solution of chloroacetyl chloride (1.0 mL, 12.6 mmol) in 1 mL of dichloromethane was added slowly into a stirred solution of trimethylsilyl (2S,4R)-4-(trimethylsilyoxy)pyrrolidine-2-carboxylate (3.62 g, 13.1 mmol) [which was contaminated with trimethylsilyl (2R,4R)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate in about 20% content] and di(isopropyl)ethylamine (3 ml, 17.2 mmol) in 100 mL of dry dichloromethane cooled on an ice bath. An additional 1.0 ml of di(isopropyl)ethylamine was added and the mixture was stirred an additional 30 minutes on the ice bath. The reaction solution was then evaporated to dryness by a vacuum pump. The residue was slurried in pentane and filtered. The filtrate was then evaporated by a vacuum pump to yield 4.26 g (96% crude yield) of crude trimethylsilyl (2S,4R)—N-chloroacetyl-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as an oil, which solidified upon cooling.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]1[CH2:28][C@H:27]1[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl.CO>[CH:1]1([CH2:6][CH2:7][C:8]2[N:16]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][CH2:28][CH:27]([OH:26])[CH2:29][O:30][C:31]4[C:39]5[NH:38][C:37](=[O:40])[NH:36][C:35]=5[CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reactant: NCCc1ccc(-n2c(CCC3CCCC3)nc3cccnc32)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cccc(OCC(O)CNCCc3ccc(-n4c(CCC5CCCC5)nc5cccnc54)cc3)c2[nH]1
Yield: 8.7 %

Procedure:
4-[2-(2-Cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.229 g, 0.68 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.141 g, 0.68 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.032 g, 0.059 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A solution of EXAMPLE 12 (0.1 g, 0.4 mmol), 3-piperidinopropionic acid (60 mg, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in N,N′-dimethylformamide (4 mL) was heated in a microwave at 100° C. for 15 minutes. The mixture was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.23-8.27 (m, 3H), 7.89 (td, J=7.8, 1.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2 Hz, 1H), 7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H), 1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1c[nH]c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (5.0 g, 52.5 mmol) and morpholine (5.0 mL, 57.8 mmol) in CH2Cl2 (160 mL) was added sodium triacetoxyborohydride (12.2 g, 57.8 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (200 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (5.3 g, 61%).