Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8](=[CH2:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:8]([CH3:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(O)(CC(C)c1cccc(F)c1OC)C(F)(F)F
Yield: 95.9 %

Procedure:
1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccccc2)cc(CN2CCN(C)CC2)c1=O
Yield: 77.1 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and N-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 77.1%).
Reaction SMILES: [C:1](ON=O)([CH3:4])([CH3:3])[CH3:2].BrCC(C)=C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)N)([O-:15])=[O:14].C(OC(C)C)(C)C>CC#N>[CH3:4][C:1](=[CH2:2])[CH2:3][C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: C=C(C)CBr
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: C=C(C)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of t-butylnitrite (0.13 ml, 1.1 mmol) and 3-bromo-2-methylpropene (0.82 ml, 8.25 mmol) in 1 ml CH3CN, 3,5-dinitroaniline (0.10 g, 0.55 mmol) was added at room temperature. The solution was stirred for 17 h at room temperature and then isopropylether was added. The suspension was filtered through a pad of Al2O3. The volatile material in the solution was removed at reduced pressure to give the title compound. 1H-NMR (CDCl3, 300 MHz) δ ppm: 8.92 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.1 Hz, 2H), 5.00 (s, 1H), 4.82 (s, 1H), 3.55 (s, 2H), 1.72 (s, 3H). 13C-NMR (CDCl3, 75.43 MHz) δ ppm: 148.4, 144.2, 142.0, 129.0, 116.9, 114.8, 43.9, 22.0.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.O1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:4]2[CH:5]=[CH:6][CH:11]=[C:2]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:3]=2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc(N3CCOCC3)c2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
The above intermediate (1.49 g, 3.51 mmol) and 1-amino-4-bromonaphthalene (0.69 g, 3.11 mmol) were dissolved in 20 mL anhydrous 1,4-dioxane in a sealable tube under inert gas atmosphere. The solution was degased and purged with nitrogen (2×). Tetrakis(triphenylphosphine)palladium(O) (0.21 g, 0.18 mmol) was added and the solution was degassed and purged with nitrogen again (2×). The tube was sealed and heated to 100° C. for 17 h. After cooling to room temperature the mixture was diluted with EtOAc, saturated aqueous potassium carbonate solution (10 mL) was added and the mixture was stirred for 1 h at room temperature. The mixture was filtered over diatomaceous earth and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 0.363 g (1.19 mmol, 38%) of title compound.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C=C(OC(=O)C(C)(C)C)C=CC=2C1)C.CN1CCC(OC2C=CC(C=O)=CC=2)CC1.[CH2:45]([N:47]([CH2:73][C:74]1[CH:79]=[CH:78][C:77]([O:80][CH:81]2[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]2)=[CH:76][CH:75]=1)[C:48]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=1[CH:56]1[CH2:65][CH2:64][C:63]2[CH:62]=[C:61]([O:66]C(=O)C(C)(C)C)[CH:60]=[CH:59][C:58]=2[CH2:57]1)[CH3:46]>>[CH2:45]([N:47]([CH2:73][C:74]1[CH:75]=[CH:76][C:77]([O:80][CH:81]2[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]2)=[CH:78][CH:79]=1)[C:48]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=1[CH:56]1[CH2:65][CH2:64][C:63]2[CH:62]=[C:61]([OH:66])[CH:60]=[CH:59][C:58]=2[CH2:57]1)[CH3:46]
Reactant: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: CN1CCC(Oc2ccc(C=O)cc2)CC1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 61.7 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-(1-methylpiperidin-4-yloxy)benzaldehyde according to an analogous synthetic method to Example 212, pivalic acid 6-{2-{ethyl[4-(1-methylpiperidin-4-yloxy)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (70 mg) was used according to an analogous synthetic method to Example 217 to provide the title compound (37 mg).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([CH2:18][CH:19]=[CH2:20])([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[CH2:18]([C:15]1([OH:17])[CH2:16][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:11]([OH:13])=[O:12])[CH2:14]1)[CH:19]=[CH2:20]
Reactant: C=CCC1(O)C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: C=CCC1(O)C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-allyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>>[OH:19][C:15]([CH3:18])([CH3:17])[CH2:16][O:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 2.5 %

Procedure:
A solution of 1.0 g (15 mmol) of 50% aqueous hydrogen peroxide in 5 mL of tert-butyl alcohol is added over 30 minutes at 60° C. to a mixture of 0.5 g (2.9 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 0.1 g (0.16 mmol) of N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(II) chloride (Jacobsen's catalyst), and 10 mL of tert-butyl alcohol. The reaction is stirred overnight at 60° C. Gas chromatography shows 2.5% of the title compound is present in the reaction mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])([O-])=O>Cl.O>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
4-Nitro-1-indanone (0.84 g, 4.75 mmol) was suspended in aqueous hydrochloric acid (9 M, 40 ml) and stannous chloride (3 g, 15.8 mmol) was added. The mixture was stirred at ambient temperature. After 2 h a clear solution was obtained. The stirring was continued for 23 h after which time a yellow precipitate had formed. The reaction mixture was diluted with water and washed trice with methylene chloride. The aqueous phase was made alkaline with 2 M aqueous NaOH and extracted four times with methylene chloride. The combined organic phases was washed with water, dried (Na2SO4), filtered, evaporated and finally dried to give the title compound (630 mg, 90%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>C1COCC1.C(O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:2]=[C:3]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:5])[N:13]=2)[CH:16]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cn2cc([N+](=O)[O-])ccc2n1
Temperature: 160 °C
Yield: 87.5 %

Procedure:
To a solution of 0.48 g of 3-bromo-1-phenylpropane-1,2-dione in a mixture of 3 mL of THF and 0.5 mL of ethanol is added 0.25 g of 2-amino-5-nitropyridine. The reaction mixture is heated for 15 minutes at 160° C. in a microwave machine. The solid formed is separated out, taken up in 3 mL of ethanol and refluxed for 6 hours. After evaporating off the solvent, the residue is taken up in ethyl acetate and diluted with sodium hydroxide solution. The organic phase is washed with water, dried and then evaporated to give 0.42 g of (6-nitroimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone in the form of a brown solid, which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: COc1ccccc1N=C=O
Product: COc1ccccc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3cnccc23)cc1

Procedure:
25 mg of solid yellow 3-{4-[3-(2-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-methoxyphenyl isocyanate.
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:7]1=[O:36])=O)C.[OH-].[Na+]>CO>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)CC(=O)NC2c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(c2ccc(Cl)cc2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Yield: 18.4 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.5 g, 0.92 mmol) was reacted with NaOH (67 mg, 1.67 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 18%).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:30].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>C1COCC1>[CH3:39][O:38][C:33]1[CH:32]=[C:37]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[C:24]2=[O:30])[CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCCCCC1=O
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Reaction time: 0.17 h

Procedure:
To 1.6 M n-BuLi in hexane (31.3 mL, 50 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (8.43 mL, 50 mmol) in anh. THF (100 mL) over 5 min. N-methylcaprolactam (6.41 mL, 50 mmol) in anhydrous THF (20 mL) was added. After stirring the reaction mixture for 10 min, a further portion of 1.6M n-BuLi in hexane (31.3 mL, 50 mmol) was added, the mixture was stirred for 10 min, and 2-chloroanisole (6.34 mL, 50 mmol) was added. After stirring for 30 min under Ar, the reaction was quenched with H2O, stirred for 30 min, concentrated in vacuo, diluted with EtOAc and washed with 5N HCl (100 mL) and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (10% EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[N:33][CH:34]=2)[CH:12]=[CH:11][C:10]=1[C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=1.Cl>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([C:25]([F:27])([F:26])[F:28])=[CH:19][C:18]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[N:33][CH:34]=2)[CH:12]=[CH:11][C:10]=1[C:45]1[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(-c2ccc(C(=O)NCCC(=O)O)nc2)c1CNc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.16 mL, 0.49 mmol) was added to a THF (1.0 mL) and MeOH (1.5 mL) solution of ethyl 3-(5-(2-(((2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)methyl)-3-methoxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate (56 mg, 0.08 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[NH2:28])[C:8]([O:10]C)=O)(=[O:4])=[O:3].CS(C1C=C(C=CC=1Cl)C(O)=O)(=O)=O.C(C1CCN(N)CC1)(OC(C)(C)C)=O.CI.C([O-])([O-])=O.[K+].[K+].[NH2:65][C:66]([NH2:68])=[NH:67]>CN(C)C=O.CO>[NH2:67][C:66]([NH2:68])=[N:65][C:8](=[O:10])[C:7]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[NH2:28])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc(N2CCC(C(=O)OC(C)(C)C)CC2N)c(S(C)(=O)=O)c1
Agent: CC(C)(C)OC(=O)C1CCN(N)CC1
Agent: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)C1CCN(c2ccc(C(=O)N=C(N)N)cc2S(C)(=O)=O)C(N)C1
Reaction time: 0.75 h

Procedure:
A solution of 550 mg of methyl 3-methylsulphonyl-4-(4-BOC-aminopiperidino)benzoate (m.p. 149°-150°) [obtainable by reacting 3-methylsulphonyl-4-chlorobenzoic acid with 4-BOC-aminopiperidine in a melt and subsequently esterifying the product with methyl iodide/K2CO3 in dimethylformamide (DMF)] and 383 mg of guanidine in 6 ml of methanol (abs.) is stirred at 60° for a period of 45 min. After removing the solvent, and after customary working-up, N-diaminomethylene-3-methylsulphonyl-4-(4-BOC-aminopiperidino)benzamide is obtained, m.p. 224°-226°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21]1>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2-c2ccc3c(c2)OCO3)cc1
Yield: 98.6 %

Procedure:
Following the general procedure outlined in Synthetic Scheme I, 2.24 g (6.45 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.39 g (8.38 mmol) of (1,3-benzodioxol-5-yl)boronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 2.47 g (99%) of 5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxole as a colorless solid: mp 110.0°-111.0° C.; NMR (CDCl3) δ 3.05 (s, 3H), 5.95 (s, 2H), 6.47-6.52 (m, 2H), 6.67(d, J=8.5 Hz, 1H), 7.16-7.24 (m, 2H), 7.32(d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H). MS (FAB): m/e 395 (M+Li). Anal. Calc'd for C20H14F2O4 S: C, 61.85; H, 3.63; Found: C, 1.92; H, 3.66.
Reaction SMILES: [F:1][C:2]([F:30])([O:9][C:10]([F:29])([F:28])[C:11]([F:27])([F:26])[O:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.[C:31]1([CH3:41])[C:32]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:31]1([CH3:41])[C:32]([S:37]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:30])[O:9][C:10]([F:28])([F:29])[C:11]([F:26])([F:27])[O:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OCCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1S(=O)(=O)CCCCCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
This hexanol (1.2 g, 2.45 Moles)was combined with toluene sulfonyl chloride (0.5 g, 2.58 mmoles), N,N-diisopropylethyl amine (0.85 mL, 4.9 mmoles), and N,N-dimethylaminopyridine (12 mg, 0.98 mmole) in dichloromethane (10 mL). After stirring for 10 hours at room temperature, the desired product, 1-toluenesulfonyl-6,6-difluoro-6-(perfluoro-2-butoxyethoxy)hexane, was isolated by column chromatography (and its structure confirmed by infrared spectroscopy).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:32]3[N:35]4[CH2:34][C:33]([OH:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: C#CC1(O)CCCNC1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(O)CCCN5C6)cnc43)cc2OC)cn1

Procedure:
7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine and 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.68 (dd, J=8.5, 2.7 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85 (dd, J=8.0, 1.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.19 (s, 1H), 5.41 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 3.43-3.41 (m, 1H), 2.94-2.91 (m, 1H), 2.85-2.81 (m, 2H), 1.91-1.84 (m, 2H), 1.74-1.71 (m, 2H) ppm; (M+1)=500.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([O:48]CC4C=CC=CC=4)=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1.[H][H]>CCO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1
Reactant: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
340 mg (0.41 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-ethoxycarbonyl methoxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL EtOH were combined with 100 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 2 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac.