Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.O=[CH:13][CH2:14][C:15]1[C:23]2[C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[C:31]1([S:28]([N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:23]=3[C:15]([CH2:14][CH2:13][NH:3][C@H:4]3[CH:9]4[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]4)[CH2:5]3)=[CH:16]2)(=[O:29])=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1cccc2c1c(CC=O)cn2S(=O)(=O)c1ccccc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A mixture of (S)-(−)-3-aminoquinuclidine dihydrochloride (202 mg, 1.01 mmol) and methyl 3-(2-oxoethyl)-1-(phenylsulfonyl)-1H-indole-4-carboxylate (330 mg, 0.92 mmol) from Step C above in 1% acetic acid in dichloromethane (20 mL) was stirred at ambient temperature for 16 h. Sodium triacetoxyborohydride (584 mg, 2.76 mmol) was added, and the resulting suspension was stirred for 2 h at ambient temperature. The solvent was removed under reduced pressure, and the crude material purified by column chromatography (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate (172 mg, 40%) as a yellow oil: MS (ESI+) m/z 468 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[O:27]1[CH2:31][CH2:30][CH:29]([CH2:32]S([O-])(=O)=O)[CH2:28]1>>[O:27]1[CH2:31][CH2:30][CH:29]([CH2:32][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:26])[CH2:16][CH2:15]3)=[CH:18]2)[CH2:28]1
Reactant: O=S(=O)([O-])CC1CCOC1
Reactant: COC(=O)c1cccc(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CC4CCOC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.1 g (0.28 mmol) of 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester (example 28, part A) and 0.72 g (0.4 mmol) of (tetrahydro-furan-3-yl)-methansulfonate. After standard purification, 0.04 g (34% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@H:24]([C@@H:30]([OH:52])[C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32]1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].N[C@H]([C@@H](O)[C@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](N2C=CC(=O)NC2=O)O1)C(OCC)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[C:37]([O:36][C@H:35]1[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[O:32][C@@H:31]1[C@H:30]([OH:52])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)[C@@H](O)[C@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (215 mg, 0.699 mmol, obtained from Reference Example 18) and a mixture of ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate and ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (300 mg, 0.699 mmol) in anhydrous tetrahydrofuran (3 ml) were stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (40 μl) and sodium triacetoxyborohydride (0.296 mg, 1.4 mmole) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the aqueous layer was separated and extracted with ethyl acetate (2×75 ml). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide ethyl (5S)-12-[(R)-[(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (230 mg, 46%) as a white solid.
Reaction SMILES: [I: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=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 126 mg of the title compound (92%) as a yellow solid in 89.18% purity by HPLC (Rt: 4.48, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21](Br)[CH:20]=[C:19]([Cl:24])[C:18]=1[O:25][CH3:26].[F-].[Cs+]>COCCOC.CCOC(C)=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>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:24])[C:18]=1[O:25][CH3:26])=[O:27]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Br)cc(Cl)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)c1OC
Temperature: 85 °C
Yield: 76.4 %

Procedure:
4-Trifluoromethylphenylboronic acid (0.815 g, 4.29 mmol) was added to a solution of 5-Bromo-3-chloro-2-methoxy-benzoic acid methyl ester (1.0 g, 3.57 mmol), Pd(PPh3)4 (0.2 g, 0.178 mmol) and CsF (1.08 g, 7.15 mmol) in DME (10 mL ) and heated at 85° C. for 10 h. The reaction was diluted with EtOAc (20 mL) and filtered, filtrate was washed water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the silicagel column chromatography gave pure 5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.94 g).
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:8](=O)[CH2:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5]>CO>[NH2:1][C:8]([CH2:9][CH3:10])=[C:3]([Cl:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: N
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: CO
Product: CCC(N)=C(Cl)C(=O)OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Dry NH3 gas is passed through a solution of 376.3 g (2.064 mol) of methyl 2-chloro-3-oxovalerate in 100 ml of methanol while stirring at 65° C. for 3 h. The solvent is removed in vacuo, the residue is taken up in diisopropyl ether, the solution is filtered through sea sand, and the solvent is evaporated. Yield: 87.6% [GC]
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].Br.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CN(C=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6]([C:5]3[CH:26]=[CH:27][N:28]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:3](=[O:2])[CH:4]=3)=[O:7])[S:10][C:11]=2[C:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1
Reactant: BrCCc1ccccn1
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccn(Cc4ccccn4)c(=O)c3)nc12

Procedure:
From 2-methoxy-N-(4-methoxy-7-morpholin-4-yl -benzothiazol-2-yl)-isonicotinamide with sodium iodide and 2-(bromoethyl)pyridine hydrobromide in DMF. ES-MS m/e (%): 500 (M+Na+, 30), 478 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.[H][H]>[Pt]=O.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C(=O)c1ccc2cc(OC)ccc2c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(C)O
Product: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1

Procedure:
Into a Paar hydrogenation bottle is added 0.144 mole of ethyl 6-methoxy-2-naphthylglyoxylate, 2 ml. of 0.1 M - ferrous sulfate solution; 220 ml. of isopropanol, and 1.0 g. of 84.1% platinum oxide. The mixture is shaken for 2 hours at room temperature with hydrogen gas until 0.144 mole of hydrogen is absorbed. The catalyst is then filtered off and the solution is evaporated in vacuo and the residue fractionally distilled to obtain ethyl 6-methoxy-2-naphthylglycolate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([N+]([O-])=O)=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[BrH:15]>>[Br:15][C:7]1[C:6]2[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Cn1c(=O)[nH]c2ccnc([N+](=O)[O-])c21
Reactant: Br
Product: Cn1c(=O)[nH]c2ccnc(Br)c21
Temperature: 135 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 20.0 g (103 mmol) 3-methyl-4-nitro-1H-imidazo[4,5-c]pyridin-2(3H)-one in 168 mL 48% hydrobromic acid was heated for 6 h at 135° C. An additional 33 mL of 48% hydrobromic acid was added and the reaction was stirred at 135° C. overnight. The reaction was cooled to room temperature and quenched into 1675 mL ice water. The resulting slurry was adjusted to pH 9 by the addition of 125 mL saturated aqueous ammonium hydroxide. The precipitate was filtered and washed with 200 mL water and dried in a vacuum oven at 50° C. overnight to give 17.58 g (75%) of the title product as a light yellow solids.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a solution of 3.9 mL (35 mmol) of 3,4-difluoronitrobenzene in 60 mL of dimethyl sulfoxide were added 9.7 mL (87.5 mmol) of N-methylpiperazine and 12.1 g (87.5 mmol) of potassium carbonate, and the mixture was refluxed for 5 hours at 100° C. The reaction mixture was cooled to room temperature and poured into 500 mL of ice water, and the resulting precipitates were collected. The collected precipitates were dissolved in 2M-HCl aqueous solution and washed with ether. The aqueous layer was neutralized with 4M-NaOH aqueous solution to give the precipitates. The precipitates were collected to give 5.71 g (68%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:4]=1[C:5]([NH:7][C@H:8]([C:10]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:13][NH:12][CH2:11]1)[CH3:9])=[O:6].CCN(C(C)C)C(C)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>C(Cl)Cl>[Cl:2][C:3]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:4]=1[C:5]([NH:7][C@H:8]([C:10]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:13][N:12]([S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[CH2:11]1)[CH3:9])=[O:6]
Reactant: C[C@H](NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(c2ccccn2)([C@H](C)NC(=O)c2ccc(Cl)cc2Cl)C1
Reaction time: 3 h

Procedure:
A sample of tert-butyl 3-{(1S)-1-[(2,4-dichlorobenzoyl)amino]ethyl}-3-pyridin-2-ylazetidine-1-carboxylate (I-4, 1.35 g, 3.5 mmol) was treated with HCl (40 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under reduced pressure to afford 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 86%) which was used without further purification. A suspension of 2,4-dichloro-N-[(1S)-1-(3-pyridin-2-ylazetidin-3-yl)ethyl]benzamide hydrochloride (1.54 g, 4.4 mmol) in CH2Cl2 (45 mL) at 0° C. was treated with i-Pr2NEt (3.1 mL, 18 mmol) and n-PrSO2Cl (0.75 mL, 6.6 mmol) dropwise. After 3 h, the reaction was quenched with the addition of 1 M aqueous NaOH (50 mL) and stirred 1 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2,4-Dichloro-N-{(1S)-1-[1-(propylsulfonyl)-3-pyridin-2-ylazetidin-3-yl]ethyl}benzamide (I-5) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[NH:11][C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[C:19]([O:35][CH2:36][CH:37]([F:39])[F:38])[C:20]([C:22]([NH:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31]([F:34])([F:33])[F:32])[CH2:27][CH2:26]3)=[O:23])=[CH:21][C:14]=2[N:13]=1>[Ni].C1COCC1>[NH2:10][CH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([O:35][CH2:36][CH:37]([F:38])[F:39])[C:20]([C:22]([NH:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([F:33])([F:34])[F:32])[CH2:27][CH2:26]4)=[O:23])=[CH:21][C:14]=3[N:13]=2)[CH:4]=1
Reactant: Cn1c(Nc2cc(C#N)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The sub-title compound was prepared in accordance with Example 3d, using 2-[(2-chloro-5-cyano-4-fluoro-phenyl)-amino]-6-(2,2-difluoroethoxy)-1-methyl-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide (210 mg; 0.37 mmol), Ra—Ni (3 mg), H2 (5 atm) and THF (10 mL). Yield: 150 mg (70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][NH2:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: N#CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Yield: 92.6 %

Procedure:
10 g of 1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbonitrile (step 1 of preparation example 1) was dissolved in 200 ml of methanol and 50 ml of ammonia (7N solution in methanol) was added, followed by 3 g of Raney Nickel. The reactor was sealed and the reaction mixture was stirred under 3 bar of hydrogen at ambient temperature for 2 hours. Then additional 5 g of Raney Nickel were added and the reaction mixture was stirred under 3 bar of hydrogen at ambient temperature for another 15 hours. Then the reaction mixture was filtered over celite and the filtrate was concentrated. Thus, 9.41 g of crude C-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-methylamine was obtained as an orange oil, which was used for the next step without further purification. 1H-NMR (CDCl3): 8.72 ppm (s, 1H), 7.90 ppm (s, 1H), 3.00 ppm (s, 2H), 1.10 ppm (s, 2H, broad), 1.00 ppm (m, 2H), 0.90 ppm (m, 2H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:18]=1[CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][C:25]1[C:17]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:18]([CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:19]([O:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[C:20]2[C:24]=1[CH2:23][O:22][C:21]2=[O:27]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Trifluoromethanesulfonic anhydride (10.57 g) was added to a solution of methyl (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate in methylene chloride (500 ml) and pyridine (5 ml) at 0° C. After 6 hours the reaction was added to excess aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:2]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16])(=[O:1])[CH3:3]
Reactant: C1CCOC1
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 0 °C

Procedure:
Tetrahydrofuran (THF) room temperature (RT), NaHCO3 solution 101.9 g (582 mmol) of 3-amino-4-chlorobenzoic acid were suspended in 700 ml of acetic acid and then admixed with 64.8 ml (687 mmol) of acetic anhydride. The mixture was heated under reflux for 15 h and, after cooling, was added to 1.5 l of ice-water. The precipitated crystals were isolated by filtration with suction, washed with water, and dried in a vacuum cabinet at 70° C. for 17 h.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[O:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=4)=[N:28][N:29]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:40][O:41][C:42]([CH3:58])([CH3:57])[C:43]([NH:45][NH:46][C:47](=[O:56])[C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([OH:55])[CH:49]=1)=[O:44]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][C:42]([C:43](=[O:44])[NH:45][NH:46][C:47](=[O:56])[C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([OH:55])[CH:49]=2)([CH3:57])[CH3:58])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[O:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=4)=[N:28][N:29]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnc(-c5ccc(O)c(O)c5)o4)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)o3)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 20 h
Yield: 78.5 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (80 mg) (0.1 mmol) and 42 mg (0.13 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 2 ml of absolute dimethylacetamide. After stirring for 20 hours the mixture is filtered and the mother liquor is concentrated at room temperature in a high vacuum. The residue is crystallized using ethanol/diethyl ether. The product is filtered off and washed with water. After drying in a high vacuum at room temperature there are obtained 65 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[C:17](=[O:18])[NH:16][C:15]2[C:19]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[N:12]1)C1C=CC=CC=1.CC(O)=O.CCOCC>Br>[NH2:10][CH:11]1[C:17](=[O:18])[NH:16][C:15]2[C:19]([CH2:23][OH:24])=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[N:12]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1NC(=O)C(NC(=O)OCc1ccccc1)N=C2c1cccc(F)c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1N=C(c2cccc(F)c2)c2cccc(CO)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of Intermediate 37G (255 mg, 0.466 mmol) in 33% HBr in HOAc (1149 μl, 6.98 mmol) was stirred at room temperature for 1 h. Ether was added and the resulting solid precipitate was collected by filtration and rinsed with ether. The solid was dissolved in MeOH (10 mL) and K2CO3 (1.3 g) was added. The mixture was stirred for 40 min. and then filtered and concentrated to dryness to afford Intermediate 37H (133 mg). HPLC: RT=1.102 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=300.2 [M+H+].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].[F:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[C:24]([F:30])[CH:23]=1.Cl>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([O:11][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:14]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][CH3:21])=[CH:18][C:13]=3[F:12])=[CH:23][C:24]=2[F:30])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCCc1ccc(-c2ccc(CBr)c(F)c2)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2ccc(COc3ccc(F)c(F)c3)c(F)c2)c(F)c1
Reaction time: 1 h

Procedure:
Into the mixture of 0.6 g (13.8 mmol) of NaH and 3 ml of dimethyl formamide (DMF), a solution of 1.8 g (13.8 mmol) of 3,4-difluorophenol dissolved in 20 ml of DMF was added dropwise, and the mixture was stirred for 1 hour. Into this mixture, 3.0 g (9.2 mmol) of 2′-fluoro-4′-propyl-3-fluoro-4-bromomethylbiphenyl was added, and the mixture was heated and refluxed for 4 hours. The reaction mixture was poured into 50 ml of 1N-HCl and extracted by 100 ml of ethyl acetate, and the obtained organic layer was washed twice with a diluted NaHCO3 solution and three times with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatograph (eluent: heptane) to obtain crude (2′-fluoro-4′-propyl-3-fluorobiphenyl-4-yl)methyl 3,4-difluorophenyl ether.