Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: Cc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2-methylphenol (10.8 g, 0.1 mmol) in acetic acid, fuming nitric acid (6.3 g) was slowly added with stirring to start reaction. The reaction mixture was stirred at a temperature of 20° C. or below for 1 h and thereafter poured into ice water. The reaction product was extracted with ethyl acetate and the extracted layer was washed with water, saturated sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in the order written. Thereafter, the washed layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography with a benzene-ethyl acetate mixture used as eluant, thereby giving the desired compound, 2-methyl-6-nitrophenol, in an amount of 1.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11](C(C3C(C4C=CC=CC=4OC)=NOC=3C)=O)[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:30][C:31](=[O:43])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=2)=[C:4]([N+:44]([O-:46])=[O:45])[CH:3]=1.B(Br)(Br)Br.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][C:5]([NH:30][C:31](=[O:43])[C:32]2[CH:33]=[CH:34][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:36][CH:37]=2)=[C:4]([N+:44]([O-:46])=[O:45])[CH:3]=1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(NS(C)(=O)=O)cc3)c([N+](=O)[O-])cc2Cl)CC1
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1
Yield: 55 %

Procedure:
N-(4-Chloro-5-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)-2-nitrophenyl)-4-(methylsulfonamido)benzamide was treated with boron tribromide as described in Example 117. The crude product (140 mg) was treated with 0.8 M trifluoroacetic acid in DCM (4.0 mL) at room temperature overnight. Solvent was evaporated in vacuo and the product was purified by preparative HPLC (0.1% TFA MeOH/H2O) to give 53 mg (55% yield) of the title compound. H1-NMR (500 MHz, CD3OD) δ 8.57 (1H, s), 8.36 (1H, s), 7.98 (2H, d, J=8.9 Hz), 7.41 (2H, d, J=8.9 Hz), 3.48-3.53 (4H, m), 3.42-3.48 (4H, m), 3.08 (3H, s).
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>C(OCC)(=O)C>[CH:11]([NH:14][C:15]([N:8]1[CH2:9][CH2:10][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:6][CH2:7]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)N=C=O
Reactant: O=[N+]([O-])OC1CCNCC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
7 g. 4-Nitroxypiperidine are dissolved in 25 ml. ethyl acetate and mixed with 5.2 ml. isopropyl isocyanate while cooling with ice water to 0°to 5° C. The reaction mixture is stirred for 2 hours at 10° C. and then evaporated in a vacuum. The residue is taken up in diethyl ether and the precipitated crystals are filtered off with suction. There are obtained 6.6 g. of the title compound; m.p. 93°-95° C., 60% of theory.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylthiophene-3-carboxylate obtained in Example (188c) (50 mg) was dissolved in acetic acid (1 mL). A hydrobromic acid-acetic acid solution (1 ml) was added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0, 10%) to obtain 20 mg of the title compound as a glassy solid (59%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]#[CH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C:10]#[CH:11])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(Cc1ccccc1)C(=O)C(C)(C)C

Procedure:
To a stirred solution of N-benzylprop-2-yn-1-amine (472 mg, 3.25 mmol) and triethylamine (493 mg, 4.88 mmol) in DCM (16 mL), cooled to 0° C. was added pivaloyl chloride (451 mg, 3.74 mmol). After 1 hour the reaction mixture was applied directly to the top of a silica gel column for purification, eluting with a gradient of 60-100% DCM in hexanes to give the title compound. MS: m/z=230 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10](S(C3C=CC=CC=3)(=O)=O)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].CO.[OH-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1
Yield: 85.5 %

Procedure:
To a stirred suspension of 5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.2 g, 33 mmol) in methanol (250 mL) powdered sodium hydroxide (2 g, 50 mmol) was added. After stirring at room temperature for 30′ more powdered sodium hydroxide (2 g, 50 mmol) and dichloromethane (50 mL) were added and stirring was prolonged for additional 30′. After concentration, a solution of 2N HCl (50 mL) and water (200 mL) was added and the obtained mixture was filtered. The yellow cake was washed with water and dried to give 5-nitro-1H-pyrrolo[2,3-b]pyridine (4.6 g, 28.2 mmol, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)[C:11](=[O:20])[CH:10]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)=[O:18])[C:11](=[O:20])[CH:10]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O

Procedure:
117 mg (0.36 mmol) of 2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 83 mg (47% of theory)
Reaction SMILES: Cl.C(OC([NH:9][C:10]1([C:23](=[O:36])[NH:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:26][CH2:27][OH:28])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)=O)(C)(C)C>O1CCOCC1.CO>[NH2:9][C:10]1([C:23]([NH:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:26][CH2:27][OH:28])=[O:36])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
Hydrogen chloride 4M in dioxane (11.72 mL, 46.87 mmol) was added to (S)-tert-butyl 4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)piperidine-1-carboxylate (Intermediate 48) (3 g, 5.86 mmol) in dioxane (30 mL). The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was dissolved in methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (1.970 g, 108%) as a colourless gum.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C:21]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23][CH2:22]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[C:25]([C:21]1([NH:20][C:6]2[N:7]=[C:8]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=2)[CH2:24][CH2:23][CH2:22]1)(=[O:26])[NH2:27]
Reactant: CC(=O)O
Reactant: N#Cc1ncc(NC2(C(N)=O)CCC2)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(NC2(C(N)=O)CCC2)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 1-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)cyclobutanecarboxamide (10 mg, 0.028 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (7 mg). MS378.2 (M+H); UV 204.8, 267.7, 297.8, 358.5 nm; t 0.423 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9](/[CH:22]=[N:23]/[O:24][CH3:25])[C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=2[CH:21]=1)(=O)=O.C([O-])(=O)C.[K+].N#N.Br[C:36]1[CH:37]=[N:38][C:39]([N:42]2[CH2:47][CH2:46][C:45]([CH3:51])([C:48]([OH:50])=[O:49])[CH2:44][CH2:43]2)=[N:40][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:19]([NH:18][C:16](=[O:17])[NH:15][C:13]1[S:14][C:10]2[C:9](/[CH:22]=[N:23]/[O:24][CH3:25])=[CH:8][C:7]([C:36]3[CH:41]=[N:40][C:39]([N:42]4[CH2:47][CH2:46][C:45]([CH3:51])([C:48]([OH:50])=[O:49])[CH2:44][CH2:43]4)=[N:38][CH:37]=3)=[CH:21][C:11]=2[N:12]=1)[CH3:20]
Reactant: CC1(C(=O)O)CCN(c2ncc(Br)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(/C=N/OC)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(/C=N/OC)c2s1
Temperature: 80 °C

Procedure:
A stirred solution of (E)-2-(3-ethylureido)-7-((methoxyimino)methyl)benzo[d]thiazol-5-yl trifluoromethanesulfonate (225 mg, 0.34 mmol), bis(neopentyl)glycolatodiboron (180 mg, 0.8 mmol) and potassium acetate (100 mg, 1.02 mmol) in anhydrous DMF (3.5 ml) was purged with N2 for 15 min. 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride (30 mg, 0.034 mmol) was added, the reaction vessel was sealed and heated at 80° C. for 2 h. The reaction mixture was cooled to ambient temperature, treated with 1-(5-bromopyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid (120 mg, 0.4 mmol) followed by aqueous cesium carbonate solution (3.7M 0.5 ml, 0.343 mmol). The reaction mixture was purged with N2 for 5 min, treated with 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride (30 mg, 0.034 mmol), sealed and heated at 80° C. for 2 h. The reaction was allowed to cool, filtered and Compound 72 purified by preperative HPLC as a brown solid (40 mg, LC-MS indicated 97% purity) (24%). 1H NMR (CH3OH-d4): δ 8.67 (2H, s), 8.40 (1H, s), 7.86 (1H, d, J=1.66 Hz), 7.53 (1H, d, J=1.67 Hz), 4.42 (2H, dt, J=13.74, 4.26 Hz), 4.11 (3H, s), 3.45-3.32 (2H, m), 2.21 (2H, dt, J=13.45, 3.31 Hz), 1.49 (2H, ddd, J=13.45, 10.71, 4.04 Hz), 1.30 (3H, s), 1.26 (3H, t, J=7.28 Hz). MS: 498 [M+H]+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].C([Li])CCC.[Cl:16][CH:17]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[C:23]=2[N:22]=1)[CH:18]([CH3:20])[CH3:19]>CCCCCC>[Cl:16][CH:17]([CH:18]([CH3:20])[CH3:19])[C:21]([NH:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[O:27])[CH2:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:3])=[O:26]
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Yield: 71.6 %

Procedure:
Using the procedure of Step A of Example 13, 10.16 g of 2-acetylaminopyridine, 106 ml of a hexane solution of n-butyllithium (1,4M) and 11.4 g of 2-(1-chloro-2-methylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one of Step A of example 3 were reacted to obtain 11.8 g of 2-[(2-chloro-3-methyl-1-oxobutyl)-amino]-β-oxo-N-(2-pyridinyl)-3-trifluoromethyl-benzene propanamide melting at 136°-138° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)(Cl)Cl>[O:27]=[C:21]([NH:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NNC(=O)CCc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The 3-phenylpropionic acid hydrazide mixture (499 mg) obtained in Production Example 22-1 was dissolved in chloroform (30 mL), and triethylamine (0.86 mL) and ethyl chloroglyoxalate (0.4 mL) were added thereto, and stirred at room temperature for 5 hours. After the reaction, the reaction liquid was entirely concentrated, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=94/6) to obtain the entitled compound (760 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([CH3:15])[C:8]=1[CH3:16])(=O)=O.[B:19]1(B2OC(C)(C)C(C)(C)O2)[O:23]C(C)(C)C(C)(C)[O:20]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.O>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([B:19]([OH:23])[OH:20])=[C:8]([CH3:16])[C:9]=1[CH3:15])=[O:14]
Reactant: Cc1c(C=O)ccc(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(C=O)ccc(B(O)O)c1C
Temperature: 90 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a solution of 4-formyl-2,3-dimethylphenyl trifluoromethanesulfonate (2.5 g) in 1,4-dioxane (50 ml) was added bis(pinacolato)diboron (2.47 g), 1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1:1) (1.09 g) and potassium acetate (2.61 g), and the mixture was stirred at 90° C. for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product in acetone (80 ml) and water (80 ml) was added ammonium acetate (1.4 g) and sodium periodate (3.95 g), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give (4-formyl-2,3-dimethylphenyl)boronic acid (560 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C1(C)C=CC=CC=1.[CH3:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(NC(=O)c3cccnc3)cnc2OCC(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
In a 25 mL sealed tube N-(5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinamide (200 mg, 532 μmol) was combined with toluene (11 mL). Under argon atmosphere, were added 3.4-dimethylbenzeneboronic acid (160 mg, 1.06 mmol), an aqueous solution of sodium carbonate (2M, 0.53 mL) and Pd(dppf)2Cl2 (12 mg, 0.016 mmol). After two hours at 90° C., the dark red suspension was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (15 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. Crystallization from ethyl acetate/heptane (5 mL, 1/2) gave a white solid (96 mg), the filtrate was evaporated to dryness and purified by column chromatography (silica gel, 20 g, 10% to 100% ethyl acetate in heptane) to get a second part of the desired product as a white solid (139 mg). Overall yield was 65%; MS (EI): 402.3 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[CH3:47][O:46][CH2:45][CH2:44][CH2:43][CH2:42][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:14]1)=[O:11]
Reactant: CCCN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCN(C(=O)c1nc2ccccc2n1CCCCOC)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
tert-Butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.97 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.93 g) was added and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-5:5) was concentrated under reduced pressure to give the object product (2.19 g).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)(=O)C>[CH3:1][CH:2]1[C:3]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:18][C:4]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNc1ccccc1
Reactant: CC1CC(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC1c2ccccc2-c2[nH]c3ccccc3c21
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
3-Methyl-1-indanone (500 mg, 3,42 mmol) prepared by an analogous method to that described by A. M. Weidler et al., Acta Chem. Scand., 18 p. 148 (1964) and phenylhydrazine (0.35 cm3, 3.5 mmol), were heated to reflux in glacial acetic acid (20 cm3). After 2 minutes concentrated hydrochloric acid (1 cm3) was added down the reflux condenser. Boiling was continued for 75 minutes and then the reaction was cooled. The solution was poured into ice/water and extracted into ethyl acetate. The extracts were washed consecutively with brine and then water, and dried (MgSO4). Evaporation of solvent in vacuo, and column chromatography of the residue (10% EtOAc/petrol [60°-80° C.]) yielded the title compound as a cream solid. Yield: 320 mg (43%). M.p. 153°-155° C. 1H NMR (DMSO-d6) δ: 1.50 (3H, d,), 3.85 (1H, q.), 7.0-7.6 (8H, m.), 11.55 (1H, s,).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[NH:18][C:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[C:22]=1[C:23]([O:25][CH3:26])=[O:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[CH:21]1[C:20]([C:35]([O:37][CH3:38])=[O:36])=[C:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[NH:18][C:17]([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2O[Si](C)(C)C(C)(C)C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl 2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (example 5, 3.90 g/6.01 mmol) in THF (39 ml) was added a solution of tetrabutylammonium fluoride (6.0 ml/6.0 mmol) at 0° C. and the resulting solution was stirred for 30 min at room temperature. The mixture was poured into water. The whole was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=4:1-2:1) to afford a yellow oil (3.20 g/99%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].C([Mg]Cl)(C)C.[Mg].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>O1CCCC1.O.CC(O)C>[NH2:24][CH:23]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)[CH2:20][CH2:21][CH2:22]1)[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCCl
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: NC(CCCO)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 3-chloropropan-1-ol (95 ml) in tetrahydrofuran cooled to below -5° C. was added over 30 minutes to a solution of isopropylmagnesium chloride [prepared from magnesium (30 g), 2-chloropropane (100 ml) and tetrahydrofuran (300 ml)]. Magnesium (36 g) was added and the mixture warmed to initiate the reaction which then had to be cooled. Tetrahydrofuran (300 ml) was then added and the mixture heated under reflux for 30 minutes. 1-(4-Chlorophenyl)cyclobutane-carbonitrile (90 g) was added and the mixture heated under reflux for 16 hours and then cooled. Sodium borohydride (30 g) and then propan-2-ol (250 ml) were added and the mixture heated under reflux for 5 hours. The reaction mixture was poured into water (1 l), and acidified with excess concentrated hydrochloric acid. The resulting acidic mixture was extracted with toluene. Removal of the toluene gave a residue which was triturated with ether to give a solid which was dried, basified and extracted with ether. The ether was removed by evaportion to give a residue which was distilled (180°/1 mm to 172°/0.8 mm) to give 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]butan-1-ol.