Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:29]([O:31]C)=[O:30])=[CH:19][N:20](COC(=O)C(C)(C)C)[C:15]3=[N:14][CH:13]=2)=[N:3]1.[OH-].[K+]>O1CCOCC1.O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:29]([OH:31])=[O:30])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a stirred solution of methyl 2-(1,6-dimethyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (1 g, 2.3 mmol) in dioxane/H2O (40 mL/10 mL) was added a solution of KOH (1.39 g, 34.5 mmol) in water (10 mL) at room temperature. Then the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was diluted with water and acidified to pH 3-4 with HCl (aqueous, 2 M). The mixture was filtered and the filter cake dried to give 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.6 g, 84.5%) as a solid, which was used in the next step without further purification. MS: (M+H)+=308.1.
Reaction SMILES: OO.[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:12]>C(O)(=O)C>[CH3:10][C:9]1[C:4]2[C:5](=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[O:12][N:3]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C(=O)c2ccc(C(F)(F)F)cc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccc(C(F)(F)F)cc3)onc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of 150 ml of 30% hydrogen peroxide and 300 ml of glacial acetic acid was heated on a steam bath for 1 hr and then cooled. The solution was treated with 26.3 g (0.094 mole) of (2-amino-3-methylphenyl) [4-(trifluoromethyl)phenyl]methanone and the mixture was heated at 70° C. for 7 hr and let stand at ambient temperature overnight. The mixture was poured into 2 liters of ice water and the solid was collected by filtration, washed with water and recrystallized from 2-propanol to yield 3.4 g (13%) of tan powder, m.p. 118°-119° C.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Br:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35]([C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:21])([F:22])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1)=[O:36]
Reactant: CON(C)C(=O)c1ccccc1Br
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 mLl (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of 2-Bromo-N-methoxy-N-methyl-benzamide (244 mg, 1.0 mmol) in 1 mL of THF. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration of the solvent the residue was purified by flash chromatograph (20% ethyl acetate in hexane) to afford 180 mg of title compound as an off white solid. MS: (M+Na)/z=621.2, (M−32)/z=567.0.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-1H-purin-6-amine trifluoroacetic acid salt (2.89 g), potassium carbonate (4.41 g) and dry DMF (32 ml) was heated at 60° C. under nitrogen for 90 minutes. Tetrahydro-3-furanylmethyl methanesulfonate (1.869 g, isomer 1) was then added and stirring continued at 70° C. for 1 h, then at 90° C. for 2 h. The solvent was evaporated and the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was purified on a 360 gm C18 column using water (+0.1% formic acid)/acetonitrile (+0.05% formic acid). Appropriate fractions were combined and evaporated, yield 814 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1cccc(CO)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)COCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of 3-methylbenzyl alcohol (1.08 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.91 g of the product 396. 1H NMR (CDCl3) δ 7.3-7.1 (m, 4H), 4.60 (s, 2H), 4.23 (q, 2H), 4.09 (s, 2H), 2.36 (s, 3H), 1.29 (t, 311); MS: m/z 209 (M++1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([NH:18][C:19]([C@H:21]4[NH:25][CH2:24][CH2:23][S:22]4)=[O:20])[S:16][CH:17]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C=O)C>[CH2:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][S:22][C@H:21]1[C:19](=[O:20])[NH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[N:14]=1)=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3NCCS3)n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3SCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C

Procedure:
A solution of (S)-thiazolidine-2-carboxylic acid [4-(4-cyclopropylcarbamoyl-phenyl)-thiazol-2-yl]-amide (50 mg, 0.13 mmol) in DMF (1 mL) was cooled to 0° C. DIEA (35 μL, 0.20 mmol) was added followed by benzyl chloroformate (30 μL, 0.21 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature over 2 hours. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 36.9 mg. MS: 509.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.55-0.74 (m, 4H), 2.80-2.91 (m, 1H), 3.10-3.27 (m, 2H), 3.65-3.75 (m, 1H), 3.90-4.04 (m, 1H), 4.94-5.17 (m, 2H), 5.51-5.55 (s, 1H), 7.06-7.41 (m, 5H), 7.79-7.98 (m, 5H), 8.41-8.48 (d, 1H), 12.50-12.60 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: BrCC1CCCCC1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCC2CCCCC2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and Bromomethyl-cyclohexane following the procedure of Example 478: MS (ES) m/z 490.3.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (910 mg), 2-methylpiperazine (320 mg), and pyridine (10 ml) was stirred at 80° C. for 1 hour. After evaporating the reaction mixture under reduced pressure, the residue was dissolved in dilute aqueous ammonia and treated with activated carbon. The filtrate was evaporated under reduced pressure and adjusted to pH 7-8. The resulting crystals were filtered, washed with water, and dried to give 1-cyclopropyl-5,6,8-trifluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (810 mg), m.p. 235°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=O)=O>>[Cl:27][C:24]1[N:23]=[CH:22][C:21]([CH2:20][O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)OCc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and (6-chloropyridin-3-yl)methyl methanesulfonate; MS: 227 (M−100).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:35])([F:34])[F:36])[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC(C)C)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 133-135° C.; 1H NMR (300 MHz, CDCl3) δ: 10.46 (1H, s), 8.40 (1H, s), 8.28-8.31 (1H, d, J=8.1 Hz), 8.04 (1H, s), 7.82-7.84 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.41-7.43 (1H, d, J=8.4 Hz), 7.34-7.36 (2H, m), 6.81 (1H, s), 6.66-6.69 (1H, d, J=9.3 Hz), 5.13-5.15 (1H, d, J=6.3 Hz), 4.08 (1H, m), 2.29 (3H, s), 1.30-1.32 (6H, d, J=6.0 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C27H23ClF3N6O: 539.1568. found: 539.1592.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27]=O)[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:33])[CH2:31][CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH2:27][NH:33][CH2:30][CH2:31][CH3:32])[CH:19]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A mixture of [3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.038 mol) in DCE (300 mL) was cooled in an ice bath to 15° C., then propylamine (0.042 mol), followed by NaBH(OAc)3 (0.057 mol) which was added portionwise. The reaction mixture was stirred overnight at room temperature and the mixture was washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 90:10 CH2Cl2:CH3OH). The product fractions were collected and the solvent was evaporated, then co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)(=O)C.C1(C)C=CC=CC=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:21]2[CH:20]=[CH:19][C:18]([OH:17])=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CCCCCc1ccc(C#Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Pentylphenylacetylene (10.5 g, 61.4 mmol), 4-acetoxyphenyl iodide (16.1 g, 61.4 mmol), a catalytic amount of Pd(PPh3)2Cl2 and a catalytic amount of copper iodide were stirred in diisopropylamine (100 ml) at 70° C. After 5 minutes, a precipitate was seen and the mixture became unstirrable, toluene (100 ml) was added. The mixture was stirred at room temperature for 24 hours and then evaporated to dryness on a rotary evaporator. The residue was redissolved in aqueous potassium hydroxide ethanolic solution and stirred at 70° C. overnight. The mixture was evaporated to dryness, then partitioned between ethyl acetate and water, the organic phase was removed, dried and evaporated. The residue was purified by flash column chromatography using DCM as eluant. A pink coloured solid was left after evaporation of the appropriate fractions. Yield=10.4 g, 64%. 1H-NMR and IR spectroscopy gave the expected signals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[Cl:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[CH3:26])=[CH:19][C:18]=2[Cl:24])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2Cl)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3C)cc2Cl)CC1
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a mixture of [4-(4-amino-2-chloro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (25 mg, 0.07 mmol), 2-methyl-benzoic acid (19 mg, 0.14 mmol), EDC (27 mg, 0.14 mmol), and HOBt (19 mg, 0.14 mmol) in DCM (5 mL) was added N-methylmorpholine (77 μL, 0.70 mmol). After 16 h, the mixture was diluted with satd. aq. NaHCO3 (10 mL) and extracted with DCM (75 mL). The organic fraction was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by SiO2 column chromatography to provide the title compound (16 mg, 46%). MS (ESI): mass calcd. for C27H28ClN3O3, 477.18. m/z found, 478.4 [M+H]+. 1H NMR (CDCl3): 7.76-7.60 (m, 1H), 7.51-7.23 (m, 8H), 7.22-7.15 (m, 2H), 6.97 (d, J=8.7, 1H), 3.66 (s, 3H), 3.15-2.93 (m, 5H), 2.85-2.49 (m, 4H), 2.42 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](N)[CH:36]=1)=[O:34]>CN(C=O)C>[C:33]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:32].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: CC(=O)c1cccc(N)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1.0 gram (g), 4.1 millimoles (mmol) is solubilized in 45 milliliters (ml) of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 microliters (μl), 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 minutes (min), and then 3-aminoacetophenone (824 mg, 6.10 mmol) and N-methylmorpholine (480 μl, 4.35 mmol) in 10 ml of DMF are added. The solution is maintained stirred at 0° C. for 2 hours (h), and then evaporated to dryness. The residue is taken up in 3 ml of MeOH, and then 50 ml of water are added. The precipitate obtained is filtered, washed with water, CH2Cl2 and ether to give 1.2 g (80%) of crude product 1a. Recrystallization from the MeOH—H2O pair gives 1a (1.01 g, 70%) in the form of a white powder.
Reaction SMILES: C(OC([NH:11][CH:12]([C:27]1[N:28]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:29]=[C:30]([CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][CH3:35])[N:31]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]([C:27]1[N:28]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH:29]=[C:30]([CH2:32][C:33]([CH3:36])([CH3:37])[CH2:34][CH3:35])[N:31]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)=[CH:16][CH:15]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd (10 wt % on activated carbon) (catalytic) was added to a degassed, ambient temperature solution of tert-butyl 2-{1-{[(benzyloxy)carbonyl]amino}-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (63 mg, 0.1 mmol) in methanol (5 mL). After stirring at ambient temperature under an atmosphere of hydrogen for 4 h, the reaction mixture was filtered through cotton and concentrated in vacuo to afford tert-butyl 2-{1-amino-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate which was used in the subsequent step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17]>>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1c(Cl)cccc1Cl
Product: O=C1CCN(Cc2c(Cl)cccc2Cl)CC1

Procedure:
1-(2,6-Dichlorobenzyl)-4-piperidone is prepared from 4-piperidone and α,2,6-trichlorotoluene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
2-Amino-3-nitrophenol (0.5 g, 3.2 mmol) was dissolved in 10 mL 2-butanone, and potassium carbonate (0.54 g, 3.9 mmol) and methyl iodide (0.4 mL) were added. The suspension was stirred overnight at room temperature. The reaction mixture was filtered through a plug of Celite, and the solid residue was washed with ethyl acetate. The resulting filtrate was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.52 g of 2-methoxy-6-nitroaniline, which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.74 (d, 1H), 6.87 (d, 1H), 6.61 (dd, 1H), 6.42 (b, 2H), 3.92 (s, 3H). MS (EI): 169 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:42][OH:43]>C(O)C>[CH2:27]([O:26][C:24]1[CH:23]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:42][OH:43])=[NH:22])=[CH:17][N:16]=1)=[O:13])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1

Procedure:
A mixture of 3,5-bis(benzyloxy)-N-(5-cyanopyridin-2-yl)benzamide (212 mg, 0.49 mmol), triethylamine (170 μL, 1.22 mmol) and hydroxylamine hydrochloride (85 mg, 1.22 mmol) in ethanol (5 mL) was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. The residue was purified by MPLC on silica eluting with 5% methanol/DCM then 15% methanol/DCM. The title compound was obtained as a colourless solid (171 mg, 75%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 5.92 (2H, s), 6.87 (1H, s); 7.28-7.48 (12H, m); 8.06 (1H, dd); 8.17 (1H, d), 8.65 (1H, s); 9.68 (1H, s); 10.85 (1H, br s); m/z (LCMS; ESI+) 469 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[O:15][CH2:16][CH2:17][O:18][CH3:19].[C-:20]#[N:21].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:9][C:7]1[CH:6]=[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=1
Reactant: COCCOc1cc(F)cc(CCl)c1OCCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(F)cc(CC#N)c1OCCOC
Temperature: 60 °C
Yield: 83 %

Procedure:
1-(Chloromethyl)-5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (0.31 g, 1.06 mmol) was dissolved in N,N-dimethylformamide (2 mL) followed by the addition potassium cyanide (0.10 g, 1.7 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (30% ethyl acetate-hexane) to provide (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.25 g, 0.88 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 6.76-6.74 (d, d, 1H), 6.66-6.63 (d, d, 1H), 4.22-4.21 (m, 2H), 4.13-4.11 (m, 2H), 3.84 (s, 2H), 3.78-3.76 (m, 2H), 3.64-3.61 (m, 2H), 3.43 (s, 3H), 3.42 (s, 3H).