Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.[CH2:21]=[O:22].[Na+].[Cl-]>C1COCC1>[CH3:12][O:13][C:14]1[N:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C=O
Reactant: COc1cccc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCO)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
1.6M n-Butyllithium/hexane solution (282 mL, 451.96 mmol) was added dropwise to a solution of 2-methoxy-6-methylpyridine (50.60 g, 410.87 mmol) in THF (625 mL) over 1 hr at −78° C. under argon atmosphere. The reaction mixture was stirred at −78° C. for 45 min, paraformaldehyde (49.3 g, 1643.49 mmol) was added thereto at −78° C., and the mixture was stirred vigorously at room temperature for 3.5 hr. The reaction mixture was poured into ice water (1000 mL), and NaCl was added thereto to give a saturated solution. The saturated solution was extracted with a mixed solvent of ethyl acetate/THF (3:1) (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 8→50% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanol (23.22 g, 152 mmol, 37%) as a colorless oil.
Reaction SMILES: [C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+](C1C=C(S(O[CH2:28][C@@H:29]2[CH2:31][O:30]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:30]1[CH2:31][C@H:29]1[CH2:28][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)(C)OC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of tert-butyl salicylate (2.01 g, 10.3 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (2.69 g, 10.4 mmol) and cesium carbonate (4.05 g, 12.4 mmol) in dimethylformamide (20 mL) was stirred at room temperture overnight. The reaction mixture was partitioned between ethyl acetetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate 40%, heptane 60%) and gave the subtitle compound (2.3 g, 89%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]\[CH3:23])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[H][H]>CO.[Pt]>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[C:17]([C:24]([F:25])([F:26])[F:27])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C/C=C\c1ccc(NC(=O)c2ccccc2NCc2ccncc2)cc1C(F)(F)F
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: CCCc1ccc(NC(=O)c2ccccc2NCc2ccncc2)cc1C(F)(F)F

Procedure:
A solution of 2-[4-pyridinylmethyl]amino-N-[4-[(Z)-1-propenyl]-3-(trifluoromethyl)phenyl]benzamide (Example 8; 0.80 g, 1.75 mmol) in methanol (25 mL) is hydrogenated at atmospheric pressure over 5% platinum on carbon (0.2 g) at 22° C. The calculated amount of hydrogen is taken up after 12 hours. The mixture is then filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% dichloromethane in EtOAc and recrystallised from diethylether-hexane to give the title compound as a colourless crystalline solid; m.p. 134–135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:15]1[C:13]2[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:32]([C:27]4[C:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:3][C:4]=3[Cl:25])=[O:7])[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[O:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A mixture of 0.263 g of 10,11-dihydro-10(4-amino-2-chlorobenzoyl)dibenz[b,f][1,4]oxazepine, 0.195 g of [1,1'-bipheny]-2-carbonyl chloride and 0.116 g of N,N-diisopropylethylamine in 7 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate (pad washed with dichloromethane). The filtrate is concentrated to dryness to give a yellow solid. The solid is purified by chromatography on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.12 g of a yellow glass, m.p. 145° C.-188° C.: Anal.found: C, 73.6; H, 4.6; N,5.0; Cl, 6.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(=O)OCC.O.CN(C=O)C>[CH3:23][O:22][C:20]([C:17]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]3[CH2:11][O:10][CH2:9]3)[CH:3]=2)[C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)=[O:21]
Reactant: Brc1cccc(C2COC2)c1
Reactant: COC(=O)c1ccc(OC)c(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(-c2cccc(C3COC3)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
1.3 g of 3-(3-bromo-phenyl)-oxetane, 1.3 g of 2-methoxy-5-methoxycarbonylphenylboronic acid, 1.3 g of Na2CO3, 69 mg of palladium(II)acetate, and 160 mg of triphenylphosphine were combined and 15 ml of DMF and 1 ml of water added. The mixture was stirred at 100° C. for 1 h and then allowed to cool to room temperature. 100 ml of EA were then added and washed three times using 30 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:3 yielded 1.3 g of the title compound, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:63])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH2:62]>[Cl-].[Na+].O.CN(C=O)C>[CH3:52][O:53][C:54](=[O:63])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][NH:62][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([CH:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[CH:14]=1
Reactant: O=C1Nc2ccc(F)cc2C1=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzoic acid (283 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 8-aminocaprylic acid methyl ester hydrochloride (251 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (333 mg, 76% yield) as a brown solid. LC-MS (m/z) 439 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+]>CO.C(#N)C>[CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc(C(=O)CN[C@H](CO)c3ccccc3)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a cooled mixture (internal temp. 2° C.) of 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanone (44.9 g) in methanol (450 ml) under nitrogen was added CaCl2.2H2O (38.7 g) in one portion resulting in a slight exotherm (max temp ˜12° C.). After the resulting clear solution had cooled to 0° C., sodium borohydride (10.5 g) was added in four portions over a 50 min period. After a further 2h at this temperature the volatile material was removed in vacuo resulting in a thick white slurry, to which ethyl acetate (500 ml) was added. The mixture was filtered through a short plug of Hyflo Supercel and the filtrate washed with water (150 ml), brine (150 ml), dried (Na2SO4) and concentrated in vacuo to give a thick orange oil. The oil was dissolved in acetonitrile (150 ml) and cooled to 5° C. for 18 h. The resulting crystals were filtered and washed with acetonitrile (3×30 ml) to give the title compound (23.9 g). The mother liquor from the filtration was concentrated in vacuo and taken up in acetonitrile (50 ml), cooled to 5° C. for 18 h to provide (after filtration and washing) a second crop of the title compound (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.CN(C=O)C.[C:26]1(B2OC(C)(C)C(C)(C)O2)=[CH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([C:11]2[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=2[C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=1
Reactant: CC1(C)OB(C2=CCCCCCC2)OC1(C)C
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(/C2=C/CCCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCCCCC2)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
To a stirred solution of 66.15D (0.750 g, 1.9 mmol) in DMF (4.00 mL, 52 mmol) at 23° C. was added (Z)-2-cyclooctenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 66.16C (0.92 g, 3.9 mmol), potassium carbonate (0.81 g, 5.8 mmol), and then tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The mixture was heated at 90° C. for 19 hours and then cooled to room temperature. The reaction was diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-10% EtOAc in hexanes) to yield 66.16D as a colorless oil (0.35 g, 49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C=O)C>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][NH:21][C:12]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccco1)c1ccc2cncc(Br)c2n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1) is stirred in DMF (20 mL) and furfurylamine (1 equiv.) is added. The reaction mixture is cooled to 0° C. (ice bath) and diethylcyanophosphonate (1 equiv.) is added followed immediately by triethylamine (2 equiv.). The reaction mixture is removed from the ice bath and stirred at room temperature for 26 hrs. The mixture is diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to afford a tan solid, which is purified via silica gel chromatography (1:1; hexanes:EtOAc to 1:3.) LC/MS (M+H) 332.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
To a solution of the product from step 1 (0.5 g, 1.6 mmol) in TFA (1 mL) was added triethylsilane (0.5 mL, 25 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 30 mL ice-water solution, neutralized with aq NaOH (2N) to pH=6-7, and then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (5×20 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (0.45 g, 85%) as a solid; 1H NMR (400 MHz, CDCl3); δ 3.78 (s, 3H), 3.87 (s, 2H), 6.82 (d, J=8.8, 2H), 7.04 (d, J=8.8, 2H), 7.07 (d, J=8.8, 2H), 7.98 (d, J=8.4, 2H).
Reaction SMILES: [C:1]([C@@H:5]([NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18](C(OC(C)(C)C)=O)[NH:19][CH3:20])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[C:1]([C@@H:5]([NH:10][C:11](=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH3:20])[CH:13]=1)[CH2:6][CH2:7][S:8][CH3:9])([O:3][CH3:4])=[O:2]
Reactant: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a solution of the product from Step G in methylene chloride was added trifluoroacetic acid (33% by volume). After stirring for 1 h the solution was concentrated in vacuo to yield the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([C:16](=[O:18])[CH3:17])[CH2:6][CH:5]1[CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14]>>[CH3:3][C:4]1([CH:16]([OH:18])[CH3:17])[CH2:6][CH:5]1[CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14]
Reactant: CC(=O)C1(C)CC1CC1CC=C(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CC1=CCC(CC2CC2(C)C(C)O)C1(C)C
Yield: 52.9 %

Procedure:
Sodium borohydride reduction of 3.0 g (13.6 mmol) of 1-[1-methyl-2-(2,2,3-trimethyl-cyclopent-3-enylmethyl)cyclopropyl]ethanone from Example 12a according to Example 11b gave 1.6 g of 1-[1-methyl-2-(2,2,3-trimethylcyclopent-3-enylmethyl)cyclopropyl]ethanol (53% yield).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>O1CCCC1>[O:7]=[C:1]([NH:11][CH2:8][C:9]#[CH:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC(=O)CCC(=O)O

Procedure:
1.6 g (16 mmol) Succinic anhydride and 1.06 g (19.2 mmol) propargylamine in 10 ml tetrahydrofuran were stirred over night at room temperature whereat a solid precipitated. The reaction mixture was taken up with methyl-t-butyl ether (MTBE) and the insoluble crystals were filtered off and dried in a stream of nitrogen. 2 g (80% of theory) of the title compound were obtained which were used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])=[CH:44][CH:43]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Beta Pharma Inc., 500 mg, 2.181 mmol) and TEA (0.912 mL, 6.54 mmol) in DCM (11 mL) was added HATU (912 mg, 2.399 mmol) followed by 4-methylbenzylamine (0.305 mL, 2.399 mmol). The resulting solution was stirred at room temperature for 48 hours. The reaction was concentrated, and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5% to 5% MeOH in DCM, to provide M5.1 in 70% yield as a white foam. 1H NMR (300 MHz, CDCl3) δ ppm 7.08-7.20 (m, 4H), 6.13 (br. s., 1H), 4.38 (d, J=5.26 Hz, 2H), 3.92 (d, J=13.30 Hz, 1H), 3.62-3.83 (m, 1H), 3.21 (dd, J=13.01, 9.65 Hz, 1H), 3.00 (dd, J=10.40 Hz, 1H), 2.33 (s, 3H), 2.20-2.30 (m, 1H), 1.80-1.95 (m, 2H), 1.58-1.71 (m, 1H), 1.43-1.52 (m, 1H), 1.42 (s, 9H); ESI-MS M+Na 355.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][O:40][C:41](=[O:45])[C:42](Cl)=O>C1COCC1>[CH3:39][O:40][C:41]([C:42]1[N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4]2[C:5]([C:8](=[O:21])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12]1)=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:45]
Reactant: COC(=O)C(=O)Cl
Reactant: CS(=O)(=O)C1CCN(CCC(=O)c2ccc(F)cc2Nc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(CN2CCC(S(C)(=O)=O)CC2)c(=O)c2ccc(F)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 1-(4-fluoro-2-phenylamino-phenyl)-3-(4-methanesulfonyl-piperidin-1-yl)-propan-1-one (500 mg) in THF (8 mL) under N2 was added NaHMDS (3.1 mL, 1 M in THF). After 5 min, chloro-oxoacetic acid methyl ester (0.28 mL) was added, and the mixture stirred for 2 h at 0° C., then for 1 h at RT. The reaction mixture was quenched with NH4Cl (sat'd aq), extracted with EtOAc, and chromatographed (0-20% MeOH/DCM) to provide 7-fluoro-3-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (301 mg, Compound 126). M+H=473; mp=190.0-191.0° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:33])([F:32])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[CH:18]=[C:17]([C:28]([F:31])([F:30])[F:29])[N:16]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>COCCOC.O>[F:33][C:14]([F:32])([F:13])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[C:18]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:17]([C:28]([F:31])([F:30])[F:29])[N:16]=1
Reactant: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a cold (-78° C.) solution of NDA, from 0.02 mol (2.8 ml) of diisopropylamine, 0.0208 mol of n-BuLi, and 30 ml of DME was added a solution of 4.65 g (0.015 mol) of product of Example 4 in 20 ml of DME. The resulting greenish solution was stirred at -78° C. for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. The reaction mixture was warmed to room temperature in 40 minutes, then poured into a mixture of 20 ml of concentrated HCl and 50 ml of water. The mixture was extracted with ether (200 ml). The ether extract was dried and concentrated. The residue was kugelrohr distilled at 13 Pa. The earlier fraction (pot temperature 50°-65° C.) was discarded. The later fraction (pot temperature 90° C.) was an oil (5.47 g) which was crystallized from hexane at low temperature to give 4.4 g (75%) of product; mp 46.5°-47.5° C.
Reaction SMILES: ClC1NC2C=C(Cl)C(Cl)=CC=2N=1.C([O-])([O-])=O.[K+].[K+].CN(C)S(Cl)(=O)=O.[CH3:26][N:27]([CH3:43])[S:28]([N:31]1[C:35]2[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:34]=2[N:33]=[C:32]1Cl)(=[O:30])=[O:29].[CH2:44]([O:46][C:47]([C:49]1[CH:50]=[N:51][NH:52][CH:53]=1)=[O:48])[CH3:45]>CN(C=O)C.O>[CH2:44]([O:46][C:47]([C:49]1[CH:50]=[N:51][N:52]([C:32]2[N:31]([S:28](=[O:30])(=[O:29])[N:27]([CH3:43])[CH3:26])[C:35]3[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:34]=3[N:33]=2)[CH:53]=1)=[O:48])[CH3:45]
Reactant: CN(C)S(=O)(=O)n1c(Cl)nc2cc(Cl)c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CN(C)S(=O)(=O)Cl
Agent: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cl)cc3n2S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,5,6-Trichloro-1H-benzoimidazole 2 (27.6 g, 0.125 mol) was dissolved in dry DMF (200 mL) and then K2CO3 (20.7 g, 0.15 mol) and dimethylsulfamoyl chloride (17.9 g, 0.125 mol) were added. The reaction mixture was stirred at room temperature for 16 hours. HPLC analysis showed the complete formation of 2,5,6-trichloro-benzoimidazole-1-sulfonic acid dimethylamide. In the same pot, without isolation of 2,5,6-trichloro-benzoimidazole-1-sulfonic acid dimethylamide, was added 1H-pyrazole-4-carboxylic acid ethyl ester (17.5 g, 0.125 mol) and K2CO3 (20.7 g, 0.15 mol). The reaction mixture was stirred at 70° C. for 4 hours and water (500 mL) was added while the reaction solution was still hot. The reaction solution was cooled to room temperature. The precipitated solid was collected via filtration, washed with water and dried. The crude product was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:27](=[O:29])[CH3:28])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)Cl
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(C(C)=O)c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.3 %

Procedure:
1-[1-(1-Methoxycarbonylpiperidin -4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (32 mg) was dissolved in 5 ml of chloroform and 9 mg of acetyl chloride and 11 mg of triethylamine were added to the solution, followed by one day's stirring at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to provide 5.1 mg of the title compound as a colorless oil.