Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15][CH2:14][CH2:13][CH2:12]C[C:7]3=[C:8]2[OH:10])=[CH:3][CH:2]=1.COC(C1CCCCC1=O)=O.N1NC(N)=CC=1>C(O)(=O)C>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[OH:10])[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:3][CH:2]=1
Reactant: Oc1c2c(nc3ccnn13)CCCCC2
Agent: COC(=O)C1CCCCC1=O
Agent: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)CCCC2

Procedure:
Using the method described for the preparation of 6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol, the reaction of 2-oxo-cyclohexanecarboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH2:16][C:17]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: CSc1ccc(N)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(NC(=O)CBr)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-(methylthio)aniline (200 mg, 1.44 mmol) in chloroform (2 ml), a saturated aqueous solution of sodium hydrogencarbonate (2 ml) was added, followed by the dropwise addition of a solution of bromoacetyl bromide (300 mg, 1.49 mmol) in chloroform (2 ml) under ice cooling. The mixture was then stirred for 1 hour. The chloroform layer was separated, washed successively with 2N hydrochloric acid (10 ml) and brine (10 ml), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby the title compound (356 mg, 95.3%) was obtained as pale brown crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:15])[CH2:7][CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][CH2:11][OH:12].N1C=CC=CC=1.Cl>>[CH3:1][S:2]([O:15][CH2:6][CH2:7][CH:8]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: OCCC(O)C(O)CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(OS(C)(=O)=O)C(CCOS(C)(=O)=O)OS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (30.4 mL) was added to a solution of hexane-1,3,4,6-tetraol (8.3 g) in pyridine (150 mol) at −45° C. After a reaction time at ice-bath temperature of three hours, the mixture was poured into hydrochloric acid (4 N). The resulting precipitate was filtered off with suction. The product with a molecular weight of 462.54 (C10H22O12S4) was obtained in this way; MS (ESI): 463 (M+H+).
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].N[CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48].C(=N)(OCC)C>C(O)C>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@H:10]2[NH2:19])[C@H:4]([O:20][C@@H:21]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([O:28][C@H:29]3[O:34][C@@H:33]([CH2:35][NH2:36])[C@@H:32]([OH:37])[C@H:31]([OH:38])[C@H:30]3[NH2:39])[C@H:22]2[OH:40])[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].[C:47]([OH:49])(=[O:48])[CH2:46][CH2:45][CH3:44]
Reactant: NCCCC(=O)O
Agent: CCOC(C)=N
Agent: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@@H]3O[C@H](CN)[C@H](O)[C@@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CCCC(=O)O

Procedure:
For acetamidylation, the neomycin B/γ-amino butyric acid conjugate obtained in Example 9a above is treated with O-ethyl acetimidate in absolute ethanol for 1-2 days, resulting in acetimidylation of the terminal amino groups. The product is purified by ion exchange chromatography, yielding neomycin B/N-acetamidino butyric acid conjugate 16.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCOC(C)=O>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: OCCOCCO
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCCOCCO
Reaction time: 0.5 h

Procedure:
A solution of 53 g of 2-hydroxyethyl ether (0.5 mol) in 200 mL of tetrahydrofuran was prepared, and the solution cooled in an ice-water bath. The solution was placed under a slow stream of argon. Sodium bis(trimethylsilyl)amide (125 mL, 0.125 mol, 1 M in tetrahydrofuran) was added dropwise over a 30 minute period. The mixture was stirred an additional 30 minutes, then 24.4 g of tert-butyl 2-bromoacetate (0.125 mol) was added. The mixture was then stirred for 1 hour. The ice-water bath was removed, and the mixture transferred to a separatory funnel using 250 mL of 1 M NaH2PO4. The mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and the solvent removed by rotary evaporator to give a clear yellow liquid. The liquid was purified by chromatography using 500 mL of silica gel and eluting with ethyl acetate/hexanes 1:1. The product was isolated as a clear, gold liquid. Obtained 5.49 g TLC Rf 0.50 (EtOAc). NMR (DMSO-d6)δ 1.42 (s, 9H), 3.42 and 3.54 (m, 8H), 3.98 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21]Cl.O>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][N:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a mixture comprising 1.94 g 1-ethoxycarbonylpiperazine and 3.45 g anhydrous potassium carbonate, in 20 mL of N,N-dimethylformamide, stirred at room temperature, under a nitrogen atmosphere, there was added 2.01 g of 2,5-dichlorobenzyl chloride. Then after 24 hr stirring at room temperature, this reaction mixture was poured into 200 mL of water, followed by extraction with ethyl acetate (3×100 mL). The obtained organic phase was dried over anhydrous sodium sulphate, followed by evaporation under vacuum. The obtained residue was then purified by flash chromatography (petroleum ether—ethyl acetate 85:15). The solvents were then evaporated off completely to give 2 g of Compound 14A (yield 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].O[C:15]([CH3:29])([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][C:6]1[C:7](=[O:9])[O:8][C:15]([CH3:29])([CH3:28])[C:16]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of 3,4-difluorophenoxyacetic acid (0.5 1 g, 2.73 mmol), 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan- l-one (0.5 g, 2.1mmol, Step 3), CMC (1.13 g, 2.73mmol) and DMAP (15 mg, 0.10 mmol) in dichloromethane (12 ml) was stirred at r.t. for 18 hrs. Then, DBU (0.63 ml, 4.2 mmol) was added and the reaction mixture was refluxed for 3 h. After cooling to r.t.the mixture was extracted with ethyl acetate and washed successively with water, IN HCl and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in a mixture of ethyl acetate and hexane affording the title compound as a solid. M.P.: 93-95° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]=[C:4]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:14])([F:15])[CH2:3][CH:4]1[CH2:5][CH2:6][C:7](=[O:8])[CH2:12][CH2:13]1
Reactant: FC(F)(F)C=C1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(CC(F)(F)F)CC1
Reaction time: 4 h

Procedure:
At atmospheric pressure, 22.0 g of 8-(2,2,2-trifluoroethylidene)-1,4-dioxaspiro[4.5]decane in 250 ml of ethanol were hydrogenated in the presence of palladium on carbon as catalyst until no further uptake of hydrogen was visible. The catalyst was subsequently filtered off and the filtrate was concentrated. The residue was taken up in 170 ml of formic acid and stirred at 20° C. to 25° C. for 4 h. The reaction solution was poured into water, adjusted to pH 8 with potassium carbonate and extracted with methylene chloride. The combined organic phases were dried with magnesium sulfate and concentrated to give the title product as a colourless oil which was reacted further without any purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([CH3:28])[C:25]([O:26][CH3:27])=[C:17]([CH3:16])[CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)nc2Cl)cc1C
Yield: 118.5 %

Procedure:
A solution of 3.2 g of 5-amino-2,4-dichloro-pyrimidine in 50 ml of ethyl acetate was added to a mixture of 25 ml of a saturated aqueous sodium hydrogencarbonate solution and 25 ml of water. A solution of 4.9 g of 3,5-dimethyl-4-methoxy-benzoyl chloride was added at room temperature over a period of 15 min. The mixture was mixed intensively for 4 h. Then the layers were separated and the aqueous layer was extracted twice with ethyl acetate. After drying over sodium sulfate and filtration, the solvent was removed in vacuo to give 7.54 g of raw product. The raw product was triturated with 25 ml of isopropanol. After filtration and washing with 10 ml of isopropanol 2.74 g of the title compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(O)C.N1C=CC=CC=1>[Cl-].[Na+].O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(O)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CON(C)C(=O)c1ccc(O)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Add 6-hydroxy-nicotinoyl chloride (11.2 g, 71 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.76 g, 79.5 mmol) to ethanol-free chloroform (100 mL, wash chloroform with water, dry over MgSO4, then filter through neutral alumina to obtain ethanol-free chloroform). Cool the mixture to 0° C. under a nitrogen atmosphere. Add pyridine (12.6 mL, 155.8 mmol), warm reaction up to room temperature and stir for 16 h under a nitrogen atmosphere. Wash reaction with water (2×75 mL) followed by brine (75 mL). Dry the organic layer over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (44:1) to obtain the desired intermediate as a yellow solid (8.6 g, 67%). MS (ES+) m/z: 183.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CO>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[N:8]=1
Reactant: CCOC(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 25 °C

Procedure:
4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester was dissolved in a mixture of methanol (150 mL) and a 33% aqueous NaOH solution (150 mL). The mixture was heated at reflux for 3 hours, and allowed to cool to room temperature overnight. The solution was concentrated to ca. half the volume under reduced pressure. The resulting suspension was adjusted to pH 7 with a 1-5N aqueous HCl solution. The formed precipitate was filtered off, washed with water (3×), and air-dried at 45° C. overnight to give 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid as a tan solid (9.051 g, 29.8 mmol, 74% over 3 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[C@H:32]([OH:33])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O[C@H](c1ccccc1)[C@H]1COCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3[C@H](O)c3ccccc3)sc21
Temperature: 95 °C
Yield: 79.3 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 134 mg) and (R)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 6, 112 mg) in DMF (3 mL) is treated with diisopropylethylamine (0.5 mL). The mixture is heated at 95° C. overnight. After cooling to room temperature, the solution is poured into ethyl acetate (75 mL) and washed with dilute pH 4 phosphate buffer (25 mL), dilute pH 7 phosphate buffer (2×25 mL), and brine (25 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (methanol/CH2Cl2, 1-3%) and ethyl acetate-hexanes crystallization to afford 0.15 g of the title compound. Physical characteristics. M.p. 171-172° C.; 1H NMR(400 MHz, DMSO-d6) δ 10.63, 8.71, 7.4-7.3, 7.3, 5.42, 5.09, 4.55, 4.50, 4.15, 3.97, 3.5, 3.4, 3.04, 2.9, 2.8, 2.4; HRMS m/z 538.1558 (M+H)+. Anal. Found. C, 62.41; H, 5.17; N, 7.73.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>ClCCl>[C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH2:11][Br:13])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: ClCCl
Product: CC(=O)c1c(O)cc(CBr)oc1=O
Reaction time: 4.5 h
Yield: 47 %

Procedure:
A mixture of 3-acetyl-4-hydroxy-6-methylpyran-2-one (52 parts), N-bromosuccinimide (54 parts) and dichloromethane (1060 parts) were stirred at 20°-25° C. for about 4-5 hours under exposure to UV light. The dichloromethane solution was washed with water (2×500 cm3) to remove the succinimide, dried over magnesium sulphate, filtered and the solvent removed at 40° C./20 mm to leave 3-acetyl-6-bromomethyl-4-hydroxypyran-2-one (70 parts, 47%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[OH-].[Li+].C(OC1C=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20]N=1)C>CC(C)CO>[CH2:22]([O:23][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH:21]([CH3:25])[CH3:20]
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC(C)COc1ccc(C(=O)O)cn1
Temperature: 35 °C
Yield: 25 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 25% yield starting from ethyl 6-chloronicotinate and 2-methylpropan-1-ol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at 35° C. over night. The product contains 58% of 6-ethoxynicotinic acid; MS (ESI) m/z 194[M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[NH:9][C:10]3[C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([CH2:42][CH2:43][CH2:44]Br)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:44][CH2:43][CH2:42][CH:38]3[CH2:39][CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37]3)[C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:10]=3[N:9]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Reactant: Clc1ccc(OCc2nc3cccc(OCc4ccccc4)c3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCc4ccccc4)cccc32)C1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was stirred at 70° C. for three hours. The reaction was quenched by the addition of water (1×30 ml). The aqueous fraction was extracted with diethyl ether (1×30 ml). The organic fractions were combined, washed with water (1×30 ml), then brine (1×30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH:14](OCC)=[O:15]>CCOCC.O>[CH:14]([CH:9]([CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:15]
Reactant: CCOC=O
Reactant: COC(=O)CCc1cccnc1
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
To a suspension of 2.1 g (90.8 mmol) of sodium in 55 mL of anhydrous Et2O is added dropwise, at 0° C. under argon, a mixture of 15 g (90.8 mmol) of methyl 3-(pyridin-3-yl)propanoate and 7.3 mL (57.41 mmol) of ethyl formate. The medium is then stirred for 12 hours at room temperature, taken up in 200 mL of water and extracted with 100 mL of Et2O. The aqueous phase is acidified to pH 5 and then extracted with 2×300 mL of EtOAc. The organic phase is then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of 0 to 10% MeOH. 4.8 g of methyl 2-formyl-3-(pyridin-3-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([N:13]([CH3:15])[CH3:14])=O)=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CN(C)C[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
Following the general procedure, reaction of 6d (3.22 g assayed, 12.0 mmol) with 1 M BH3 in THF (42.0 mL, 42.0 mmol) afforded 7d in an assayed yield of 2.21 g (8.7 mmol, 73% assay yield, 99% peak area). A sample was concentrated in vacuo to an oil to provide the standard.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:20][CH:19]([C@H:17]1[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C(C)C)C3=O)cc2)ccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 174.4 %

Procedure:
To a solution of N1-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-D-valinamide (Intermediate 83, 65 mg) in dry dichloromethane (10 mL), TEA (0.138 mL, 0.990 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (26.4 mg, 0.089 mmol) in dry dichloromethane (3 mL) was slowly added and the reaction mixture was stirred for 1 hour at 0° C. The reaction was quenched with water (2 mL) and a saturated aqueous solution of ammonium chloride (5 mL) and was extracted with dichloromethane (2 times 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel flash chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl from 100/0 to 60/40 to afford the title compound as a white solid (55 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].[C:20]([Li])(C)(C)C.CN(C=O)C>C1COCC1>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[CH:18]=[CH:20]1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2ccc(C(C)(C)C)cc21
Temperature: 25 °C

Procedure:
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester (prepared in Example CC; 19.7 g, 75 mmol) in 100 mL of THF was cooled to −40° C. To it was added tert-butyllithium (1.5 M, 100 mL, 150 mmol), dropwise with stirring, at −45° C. to −35° C. After the addition was complete, the reaction was stirred at −35° C. for another 15 minutes. DMF (10.97 g, 150 mmol) was added dropwise, and the reaction mixture was stirred at −35° C. for 30 minutes, followed by slow warming to room temperature. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was dissolved in 100 mL of THF and 2 mL of concentrated HCl and stirred at room temperature for 1 hour. EtOAc was added, and the solution was washed with saturated NaHCO3 solution and brine and dried (MgSO4). Concentration gave a residue that was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes). MS(APCI): 274 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5][CH2:4]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(C#N)CC2)CCOCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN2CCC(CN)CC2)CCOCC1
Yield: 97.9 %

Procedure:
A mixture of tert-butyl 4-[(4-cyanopiperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate (5.76 g, 0.0187 mol, step 4) and Raney Ni (3.00 g) in methanol (100 mL) was hydrogenated (3 atm) at room temperature for 12 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 5.72 g (98%) of the title compound as a yellow syrup.