Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](OCC1C=CC=CC=1)[C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][C:4]1=2.B.O1CCCC1.O>O1CCCC1>[CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CN(OCc1ccccc1)C1(C)CCCc2nc(OCc3ccccc3)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 70.5 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-N,2-bis(phenylmethoxy)-5-quinolinamine (12.3 g) in tetrahydrofuran (160 ml) at 0° C. was treated dropwise with borane-tetrahydrofuran complex (1M in tetrahydrofuran, 63.4 ml). The solution was heated under reflux for 3 hrs, cooled to 0° C., and water (30 ml) was added. The reaction mixture was concentrated in vacuo, 20% potassium hydroxide solution (60 ml) was added, and the mixture was heated at reflux for 2 hrs. The mixture was cooled, acidified with conc hydrochloric acid, and washed with diethyl ether. The aqueous phase was basified with 20% potassium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated to afford 6.3 g (92%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([OH:20])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:21]CN(C(C)C)C(C)C.[Si](C=[N+]=[N-])(C)(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([O:20][CH3:21])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Oc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol (38 mg, 0.126 mmol, 1.0 equiv) in DCM (3.0 mL) and MeOH (1.0 mL) was added DIPEA (0.188 mmol, 1.5 equiv) then TMSCHN2 (94 microliter, 0.188 mmol, 1.5 equiv). The reaction mixture was stirred at rt for 3 h, then quenched with water and extracted with ethyl acetate. Purification by column chromatography using 20% ethyl acetate in hexanes elution gave 20 mg of the yellow solid, 50%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:18][C:19](=[O:47])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:47])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[O:12][CH2:13][O:14][CH3:15])=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH3:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COCOc1cccc(OC)c1B(O)O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
6-Methoxy-2-methoxymethoxybenzeneboronic acid (1.92 g) was coupled with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine ethyl ester in a similar procedure as described in Example 5-3) to afford N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-methoxymethoxyphenyl)-L-phenylalanine ethyl ester (0.942 mg). ESMS m/Z 532 (MH+), 530 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].O>CN(C=O)C>[CH3:19][N:20]([CH3:24])[C:21]([O:18][C:5]1[C:4]([CH3:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1)=[S:22]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1OC(=S)N(C)C)C(C)(C)CCC2(C)C

Procedure:
In a round bottom flask there are introduced 1.7 g (57 mmoles) of sodium hydride (80% in oil) and 50 ml of dimethylformamide. There is slowly added a solution of 10.3 g (47 mmoles) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol in 100 ml of DMF and the reaction mixture is stirred until the cessation of gas evolvement. There are then added 8.1 g (66 mmoles) of dimethylthio-carbamoylchloride in 100 ml of DMF and the reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethylether. The organic phase is decanted, washed with water, dried on MgSO4 and the solvent evaporated. The residue is purified by chromatography on a silica column (eluant: 20/80 mixture of CH2Cl2 /hexane). 13.2 g (92%) of 2-(N,N-dimethylthiocarbamoyloxy)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 102-103° C. are recovered.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].C(O)(=O)C.[CH3:23][O:24][C:25](=O)[O:26]C>>[Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH2:8][C:25]([O:24][CH3:23])=[O:26]
Reactant: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: 95 °C
Yield: 41 %

Procedure:
To a solution of 1-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanone (Preparation 63, 9.53g) in dimethylcarbonate (200 mL) is added NaH (1.53 g; 60% dispersion in mineral oil) portionwise at ambient temperature. The reaction mixture is heated to 95° C. for 3 h. The reaction vessel is cooled to ambient temperature and the mixture is poured into ice cold water (500 mL) containing acetic acid (15 mL). The aqueous layer is extracted with Et2O (3×100 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude brown liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 4.77g (41%) of the title compound as a tan solid. Physical characteristics: m.p. 67-68° C.; 1H NMR (300 MHz, CDCl3) δ 7.21, 3.99, 3.78, 3.71, 3.60, 2.50; IR (diffuse reflectance) 2822, 1738, 1663, 1461, 1399, 1350, 1336, 1316, 1286, 1265, 1156, 1113, 1009, 1004, 864 cm−1; MS (ESI+) m/z 318; Anal. Found: C, 48.89; H, 5.13; N, 4.45.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:4]1[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]=1[OH:16]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
In 500 mL roundbottom flask, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (10.2 g, 46.72 mmol) was dissolved in 100 mL Acetic Acid. To this solution Bromine (8.2 g, 51.39 mmol) was added. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])C(OC)=O)[CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH2:19][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])[CH:3]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc([N+](=O)[O-])cc3F)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
358 mg (0.72 mmol) of methyl (6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)(2-fluoro-4-nitrophenyl)acetate are dissolved in 6 ml of methanol. 21 mg (0.87 mmol) of lithium hydroxide and 2 drops of water are added, and the mixture is stirred at RT for 20 hours. The mixture is concentrated under reduced pressure, dichloromethane and water are added and the organic phase is separated off and dried over sodium sulfate. The solvent is removed under reduced pressure and the product is purified by chromatography on silica gel (mobile phase: dichloromethane). This gives an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)(O)[O-:13].[Na+].O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8][OH:13])[CH:7]=1
Reactant: Cc1cc(Br)cc(CBr)c1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(CO)c1F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred solution of 5-bromo-1-(bromomethyl)-2-fluoro-3-methylbenzene (6.56 g, 23.3 mmol) in acetone (150.0 mL) was added sodium bicarbonate (2.44 g, 29.1 mmol) and water (250.0 mL). The reaction was refluxed overnight. The reaction was cooled to room temperature and extracted 3× with ethyl acetate. The organic extracts were combined and washed with brine, dried over sodium sulfate and concentrated. The resultant oil was flash chromatographed (80 g silica, 5-10% ethyl acetate/hexanes gradient) to yield 2.5 g of (5-bromo-2-fluoro-3-methylphenyl)methanol as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCn1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 35.6 %

Procedure:
The title compound (47 mg) was prepared according to Example 193 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 218 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C16H18N4, 266.15. found, m/z 267.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93-7.91 (m, 2H), 7.58-7.56 (m, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.43-3.40 (m, 2H), 3.18-3.16 (m, 2H), 2.82-2.80 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N+:12]=[N-:13]>CO>[N:11]([C:14](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[Cl:2])[C:15]([O:17][CH3:18])=[O:16])=[N+:12]=[N-:13]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccccc1Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccccc1Cl)N=[N+]=[N-]
Temperature: -18 °C
Reaction time: 3 h

Procedure:
Sodium pieces(3.678 g, 160 mmol) were added in portions to methanol (200 ml) over a 30 minute period. The resulting solution was cooled in a dry ice/acetone bath to −18° C. and then over one hour a mixture of 2-chlorobenzaldehyde (4.832 g, 40 mmol) and methyl azidoacetate (160 mmol) was added at a rate that maintained the temperature below −15° C. After three hours, the solution was stored at 5° C. for two days to give crystalline material which was collected by filtration and washed with cold hexane to give pure product as a yellow crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)CCC(=O)O
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 84%), MS (ISP) m/z=429.5 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1>CN(C=O)C>[Si:35]([O:29][C@@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:13])([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-nitrobenzo-hydrazide (2.0 g, 4.63 mmol) was added to DMF (100 mL), followed by addition of TBDMS-Cl (1.74 g, 11.6 mmol) and imidazole (1.58 g, 23.2 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 minutes and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extract with EtOAc. Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white solid (780 mg, 82%). 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.88 (br s, 2H), 8.35 (d, J=6.7 Hz, 2H), 8.16 (d, J=6.7 Hz, 2H), 7.53 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.56 (d, J=6.6 Hz, 1H), 4.46-4.36 (m, 1H), 4.18-4.10 (m, 1H), 3.26 (s, 3H), 1.37 (d, J=7.4 Hz, 3H), 0.94 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1([NH:8]/[C:2](/[CH3:1])=[CH:3]\[C:4](=[O:6])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)/C=C(/C)Nc1ccccc1

Procedure:
A solution of 2,4-pentanedione (51.5 mL), aniline (45.6 mL) and a catalytic amount of para-toluenesulfonic acid monohydrate (0.95 g) in toluene (500 ml) was refluxed for 3.5 h in a round bottom flask equipped with a Dean-Stark apparatus and condenser. The solution was concentrated to dryness to give the desired compound as an orange oil (89.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]-amide (AMR01038, 100 mg, 0.274 mmol) in dry DCM (10 mL) were added pyridine (0.044 mL, 0.548 mmol) and benzoyl chloride (0.047 mL, 0.411 mmol). The reaction mixture was stirred at room temperature until TLC showed consumption of starting material (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-benzoylpiperidine-4-carboxylic acid [2-(2,4-dichloro-phenoxy)phenyl]amide (98 mg, 76%) as a white solid, mp 176-177° C. Rf: 0.17 (hexane/EtOAc 1:1) LC/MS (APCI) tr=1.10 min, m/z 471.26 (58), 469.31 (M++H, 100) HPLC tr=2.88 min (99.48%) 1H NMR (270 MHz, CDCl3) δ 1.85 (4H, m, 2CH2), 2.55 (1H, tt, CH), 3.01 (2H, m, CH2), 3.89 (1H, m, ½CH2), 4.74 (1H, m, ½CH2), 6.72 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.95 (1H, d, J=8.6 Hz, ArH), 7.01 (1H, td, ArH), 7.14 (1H, td, ArH), 7.22 (1H, dd, J=8.6, 2.5 Hz, ArH), 7.39 (5H, s, ArH), 7.49 (1H, d, J=2.5 Hz, ArH), 7.78 (1H, br s, NH) and 8.38 (1H, br d, J=8.2, ArH). Anal. Calcd. for C25H22Cl2N2O3: C, 63.97; H, 4.72; N, 5.97. Found: C, 64.10; H, 4.83; N, 5.88%.
Reaction SMILES: [F:1][C:2]([F:32])([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][CH:4]1[CH2:8][CH:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:5]1=[O:17].C1C=CC(S)=CC=1.[Li]CCCC.C1C[O:48]CC1>>[F:1][C:2]([F:32])([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][CH:4]([CH2:8][CH:7]([OH:48])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:6])=[O:17]
Reactant: C1CCOC1
Reactant: COc1ccc(-c2ccc(C(F)(F)CC3CC(CSc4ccccc4)OC3=O)cc2)cc1
Agent: Sc1ccccc1
Agent: [Li]CCCC
Product: COc1ccc(-c2ccc(C(F)(F)CC(CC(O)CSc3ccccc3)C(=O)O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
3-[2,2-Difluoro-2-(4′-methoxy-biphenyl-4-yl)-ethyl]-5-phenylsulfanylmethyl-dihydro-furan-2-one. A solution of phenylthiol (0.65 mmol) in THF (5 mL) is treated with BuLi (0.65 mmol) at −20° C. After being stirred for 20 min at −20° C., Example 18d (0.5 mmol) in THF (5 mL) is added dropwise. The mixture is allowed to warm to 0° C. and kept at that temperature for 2 hours, then is warmed up to room temperature and stirred for 3 hours. The reaction is quenched with saturated NH4Cl, neutralized with 1N HCl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude material obtained after evaporation of solvents is purified by flash chromatography (3/1 hexane/acetone) and recrystallized from hexane/acetone to give the desired compound as colorless needles: mp 117-118° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:6]=[CH:7][C:8]=1[F:13])#[N:11]
Reactant: N#Cc1cc(C(=O)CBr)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(Bromoacetyl)-2-fluorobenzonitrile (590 mg, 2.44 mmol) and (S)-4-N—BOC-2-hydroxymethyl-piperazine (527 mg, 2.44 mmol) were dissolved in THF (40 mL) at 0° C. then TEA (247 mg, 2.44 mmol) was added. The reaction mixture was stirred at RT for 16 h, then poured into water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by MPLC through an 80 g Redi-sep column using 0-100% EtOAc/hexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:34]/[OH:35])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(S(C)(=O)=O)C3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(S(C)(=O)=O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-1-(2-methylpyridin-4-yl)-3-(4-(1-(methyl-sulfonyl)azetidin-3-yl)phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=464.1 ([M+H]+).
Reaction SMILES: [CH3:1][NH:2][C:3]([F:5])=[O:4].[Cl:6][C:7]([Cl:11])([Cl:10])[S:8]Cl.CCOP(OC1C=CC2C(C)=CC(OC=2C=1)=O)(OCC)=S>>[CH3:1][N:2]([S:8][C:7]([Cl:11])([Cl:10])[Cl:6])[C:3]([F:5])=[O:4]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CNC(=O)F
Agent: CCOP(=S)(OCC)Oc1ccc2c(C)cc(=O)oc2c1
Product: CN(SC(Cl)(Cl)Cl)C(=O)F

Procedure:
N-Methyl-N-trichloromethanesulfenylcarbamoyl fluoride was prepared from methylcarbamoyl fluoride and trichloromethanesulfenyl chloride according to the method reported in West Germany Pat. No. 1.297,095 (Farbenfabriken Bayer, A. G), June 12, 1969.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)=[N:7]2
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was prepared from 5-bromo-2-chloroquinoline and 5-methyl-2-furanmethanamine as described in example 1 step A.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(I)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (4-iodophenyl)methanamine (5 g, 18.5 mmol) and benzyl chloroformate (3.47 g) in a mixture of tetrahydrofuran (20 mL) and H2O (50 mL) was added K2CO3 (10.2 g, 74 mmol) at 5° C. The reaction mixture was stirred at room temperature for 5 hours, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound. LC-MS (ESI): m/z 368 (M+H), RT: 2.25 min; 1H NMR (400 MHz, CDCl3): δ 4.32 (d, J=6.0 Hz, 2H), 5.13 (s, 2H), 7.03 (d, J=7.6 Hz, 2H), 7.32-7.36 (m, 5H), 7.65 (d, J=8.0 Hz, 2H).