Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15](O)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([Cl:21])=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Yield: 95.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), SOCl2 (330 mg, 2.78 mmol) and one drop of DMF in toluene (30 mL) was refluxed for 2 h. The mixture was concentrated under vacuum to afford crude 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (200 mg, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>ClCCl.O>[CH3:19][O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccc(Br)c(C)c1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To a solution of 10.00 g 4-bromo-3-methylaniline in 50 ml dichloromethane was added 80 ml of a 10% solution of sodium bicarbonate in water. The mixture was cooled to 0° C. and 6.2 ml (7.62 g) methyl chloroformate was added during 10 min. with stirring. The reaction mixture was stirred at room temperature for 1 h. The phases were separated. The organic phase was washed with a 10% solution of citric acid in water, 10% solution of sodium bicarbonate in water and brine, dried with magnesium sulfate and evaporated to yield 12.94 g of (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester as light brown solid melting at 71–72° C.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)C1C=CC=CC=1>CCCCCC.C1COCC1>[CH:34]1([C:32]2([CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=3)[O:33][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.6 g (99.9 mmol) of methyl acetoacetate, 4.19 g (105 mmol) of NaH (60% dispersion in oil), 64.0 mL (102 mmol) of 1.6 M n-butyl lithium in hexane, 16.1 g (49.9 mmol) of 3-(4-benzyloxy-phenyl)-1-cyclohexyl-propan-1-one (prepared in Example G) and 550 mL of THF. After addition of the ketone, the reaction was stirred for 120 minutes at 0° C., then 1 hour at room temperature. The reaction was quenched with acetic acid (12 mL) and worked up in the usual manner. The crude product was carried on without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>O.[Pt](=O)=O.CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: OCc1ccc2ncccc2c1
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: OCc1ccc2c(c1)CCCN2
Reaction time: 2 h
Yield: 68.7 %

Procedure:
6-Hydroxymethylquinoline (1 g, 6.28 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and methanol (200 mL) were placed in a Parr bomb and platinum (IV) oxide monohydrate (0.5 g, 2.04 mmoles) was added. The mixture was hydrogenated at 50 psi at 25° C. for 2 h. The catalyst was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (0.7044 g, 68%): CIMS: m/z 164.35 (MH+); δH (CDCl3) 1.93 (2H, m, 3-CH2) and 2.76 (2H, t, 4-CH2), 3.30 (2H, m, 2-CH2), 4.50 (2H, s, CH2OH), 6.45 (1H, d, Ar—H8), 6.96 ppm (2H, m, Ar—H5 and Ar—H7); δC (CDCl3) CH2: 22.1, 27.0, 42.0, 65.6; CH: 114.2, 126.4, 129.2; C: 121.5, 129.4, 144.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)=[O:20])([CH3:17])[CH3:16]
Reactant: Nc1ccc(CC2CCNCC2)cc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3 mmol) in dichloromethane (20 mL) was cooled in an ice bath under nitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was added dropwise to the solution and stirred at ice bath temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacuo. The crude product was chromatographed on silica gel, eluting with 2% methanol/dichloromethane containing 0.01% ammonium hydroxide, to give 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g, 80%) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([Cl:16])=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(O)c1cn2cc(F)ccc2n1
Reactant: O=S(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn2cc(F)ccc2n1

Procedure:
To a suspension of the product of step (b) (20 g) in toluene (250 ml) and tetrabutylammonium chloride (0.3 g) was added thionyl chloride (40 ml) and the mixture refluxed for 4 hrs. A further aliquot of thionyl chloride-(40 ml) was added and the mixture was refluxed for a further 4 hrs. Solvents were evaporated and the residue was azeotroped with toluene to give the sub-title compound as a solid (20 g). This was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH:15]1OCCO1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:20]([O-:24])(=[O:23])(=[O:22])=[O:21].[Na+]>O>[Cl:20]([O-:24])(=[O:23])(=[O:22])=[O:21].[CH3:14][C:13]1[N+:9]2=[CH:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH:15]=[C:10]2[S:11][CH:12]=1
Reactant: Cc1csc(C2OCCO2)[n+]1Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: Cc1csc2cc3ccccc3c[n+]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 25 g of polyphosphoric acid heated at 110° C. was added with stirring 3-benzyl-2-(1,3-dioxolan-2-yl)-4-methylthiazolium bromide (2.31 7 g, 7.9 mmol) and the mixture was stirred for 3 h. The mixture was cooled to room temperature, poured into 200 ml of water, and treated with 3 g of sodium perchlorate. The precipitated product was filtered, washed with water, ether and dried in vacuo to afford 1.5 g (64%) of 3-methylthiazolo[3,2-b]isoquinolinium perchlorate (Formula II: A=3-methylthiazolo;R1 =R6 =H; X- =ClO4-).
Reaction SMILES: C(Cl)CCl.ClC1C=CC(C(NC2C=CC(OC)=CC=2)C(F)(F)F)=C(C=1)C[NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[C:35]([OH:45])(=O)[C@@H:36]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[OH:37].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[CH:38]1([C@@H:36]([OH:37])[C:35]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:19])=[O:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(O)[C@H](O)C1CCCCC1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)(F)F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Reaction time: 16 h
Yield: 116.4 %

Procedure:
EDC (44.0 mg, 0.23 mmol) was added to a stirred mixture of N-(5-chloro -2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-L-prolinamide (68 mg, 0.15 mmol), (R)-(−)-hexahydromandelic acid (24.2 mg, 0.15 mmol) and HOAT (10.4 mg, 0.076 mmol), in DMF (2 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (eluting with EtOAc/CHCl3, 1:2) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl)}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (44.4 mg) as a glass: MS: 582.4 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30]C(=O)OCCCC)=[N:28][CH:29]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[CH:25][CH:26]=1
Reactant: CCCCOC(=O)Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a cooled (0° C.) suspension of tent-butyl {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate (0.27 g, 0.53 mmol) in anhydrous dichloromethane (12 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at ambient temperature for 3 h and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate (35 mL) and brine (35 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1-′[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.20 g, 93%) as a colorless solid: mp 117-119° C.; 1H NMR (300 MHz, DMSO-d6) 8.00-7.96 (m, 1H), 7.37-7.24 (m, 2H), 7.19-7.07 (m, 2H), 7.07-6.98 (m, 1H), 6.52 (s, 1H), 6.43-6.38 (m, 1H), 6.01-5.96 (m, 3H), 4.82-4.62 (m, 4H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 159.2, 154.6, 147.0, 144.1, 141.9, 137.7, 136.7, 131.7, 128.7, 123.5, 122.9, 121.2, 119.3, 110.7, 109.4, 108.0, 98.7, 79.2, 64.1, 63.5, 57.1; MS (ES+) m/z 401.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])=[O:9]
Reactant: Cn1nccc1-c1cc(C(=O)O)c(Cl)n1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 2-chloro-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (0.116 g, 0.48 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.186 g, 0.48 mmol)[prepared according to Preparation 5] and N,N-diisopropylethylamine (0.42 ml, 2.42 mmol) in dichloromethane (2.49 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.25 g, 0.53 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (250 mg, 0.38 mmol, 78% yield) as a clear oil: LCMS (ES) m/e 570, 572 (M, M+2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:29]5[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[N:30]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n1
Yield: 72.3 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 6-methylpyridine-2-carboxylic acid (66 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (100 mg, 72%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccncc1
Reactant: Nc1ccc(F)cc1C(=O)O
Product: O=C(O)c1cc(F)ccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-5-fluorobenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 168.9, 152.4, 149.6, 148.8, 147.2, 121.9, 121.6, 116.6, 113.0, 110.7, 44.9.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CC3CCCCC3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.3 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0843 g, 0.183 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.127 mL, 0.913 mmol) and cyclohexylmethanesulfonyl chloride (0.108 g, 0.548 mmol) to obtain 4-cyclohexylmethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 80%).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([O:16]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([NH2:2])=[O:16])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1scc(Br)c1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1c(Br)csc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (10 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-4-bromothiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (250 mg, 53%), mp 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (1H, s), 7.75 (1H, br s), 7.56 (1H, br s), 3.56 (3H, br s), 3.21 (3H, br s); LC-MS (positive ion mode): m/z 277, 279 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH3:17])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:18]([N:16]([CH3:17])[CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[CH:12][CH:11]=3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)C(=O)O

Procedure:
3-(4-[2-([10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]-methyl-amino)-ethoxy]-phenyl)-2-ethoxypropanoic acid ethyl ester (example 10)(1.5 g, 3.07 mmol) was dissolved in ethanol (20 ml) and 20% sodium hydroxide (2 ml) was added. After 6 days ethanol was evaporated in vacuo, water (50 ml) and acetic acid (2 ml) were added and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue (1.4 g) was dissolved in acetone and neutralized with solution of hydrogen chloride in diethyl ether. The solvents were evaporated and the residue was triturated with diethyl ether yielding 1.15 g (74%) of the title compound as amorphous solid (hemihydrate). 1H NMR (250 MHz, DMSO-d6) δ10.50 (bs, 1 H); 7.60 (bs)+7.10-7.50 (m, 10 H), 6.87 (d, J=7.9 Hz, 2 H), 5.84 (bd, J=7.0 Hz, 1 H), 4.49 (bs, 2 H), 4.00 (t, J=5.6 Hz; +bm, 3 H), 3.30-3.60 (m+m, 4 H), 2.80-3.10 (s+bm, 7 H), 1.07 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 65.7 %

Procedure:
2.0 g Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (8.6 mmol) and 2.89 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.3 mmol) were dissolved in a mixture of toluene (20 ml) and ethanol (50 ml) 0.35 g of dichloro (1,1′bis-(diphenylphosphine)ferrocene)palladium(II)dichloromethane (0.43 mmol) was added and heated to 85° C. Then aqueous sodium carbonate (2M) (10 ml) was added and the reaction kept at 85° C. for 45 min. After cooling to ambient temperature the reaction was extracted with ethyl acetate/water, the organic phase was dried over sodium sulfate and concentrated. Column chromatography on silica gel (n-heptane/ethyl acetate 4:1) yielded 1.33 g of 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (66%) as a yellow solid; M.p.: 117–120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:7]1[C:6]2[CH:18]=[C:2]([C:30]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][CH:29]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)c(F)c1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4F)c3c2)cc1

Procedure:
The title compound, light brown solid (69 mg, 55%), MS (ISP) m/z=391.5 [(M+H)+], mp 152° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(2,4-difluoro-phenyl)-1H-benzo[d]imidazole (intermediate K) (100 mg, 324 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (79.9 mg, 388 μmol).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:16]C(=O)OCC1C=CC=CC=1)[CH3:15].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:16][CH:14]([C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:15]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(N)c1nc2ccc(F)cn2c(=O)c1Br
Reaction time: 0.83 h
Yield: 104.9 %

Procedure:
E2 (312 mg, 0.74 mmol) was dissolved in 18 mL of anhydrous dichloromethane. BBr3 (3.7 mL, 1M in dichloromethane) was added dropwise at −10° C. under nitrogen. Stirring was continued at −10° C. for 50 min., then at room temperature for 45 min. Water was added to quench the reaction. The dichloromethane layer was set aside. The aqueous layer was adjusted to pH 8 with sodium bicarbonate and extracted with 30% isopropanol in chloroform 4 times. The dichloromethane layer was washed with brine and the brine layer was adjusted to pH 8 with sodium bicarbonate and extracted with 30% isopropanol in chloroform 1 times. The combined 30% isopropanol in chloroform extracts were dried and concentrated to give 222 mg of E3 as a solid, which was used directly for next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH2:15])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(O)C(N)(CO)CO.Cl>C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH:15][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(N)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(NC(=O)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
The material from step 2 was suspended in a mixture of diisopropyl ethyl amine (0.15 mL), PS-DMAP resin (50 mg), 2,2-dimethylpropanoyl chloride (0.1 mL) and dichloromethane (7 mL). The reaction was agitated overnight and then treated with PS-Trisamine resin and agitated a further 24 h. The reaction was applied to an Extrelut QE column prepped with 1N HCl, the organic was collected and evaporated under a stream of nitrogen. The residue was chromatographed on silica to afford the title product. MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.