Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[Cl:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:26][N:13]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:10]=[C:9]1[C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1cccc(Cl)c1-c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(Cl)c1-c1nc(-c2ccccc2)c(-c2ccccc2)n1Cl

Procedure:
A mixture of 14.60 g. (0.04 mole) of the 2-(2',6'-dichlorophenyl)-4,5-diphenylimidazole, 5.34 g. (0.04 mole) of N-chlorosuccinimide, and 400 ml of carbon tetrachloride was heated at reflux temperature for 2 hours. The solution was cooled, filtered, and thefiltrate concentrated under vacuum. The resulting solid-oil mixture was triturated with 1-chlorobutane to give a residue of 16.68 g., m.p. 120°-140° C. (broad). The compound proved difficult to recrystallize from common solvents and only acetonitrile and nitromethane afforded reasonable recovery of crystals; from the latter solvents the crystals formed as large chunky aggregates. The best fraction 0.7664 g. has m.p. 125°-127° C.; an IR spectrum showed no NH absorption and a very strong 1620 cm-1 band.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:50]=[N+:51]=[N-:52])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[C:21]([CH3:30])([CH3:29])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
(2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) was dissolved in anhydrous DCM (3.87 mL) and cooled in an ice bath. Triethylamine (0.27 mL, 1.94 mmol) was added followed by toluene-4-sulfonyl chloride (148 mg, 0.77 mmol). Reaction was stirred for 1 h at 0° C. (ice bath) and gently warmed to ambient temperature over 18 h. The solvent was removed in vacuo and residue purified by column chromatography on silica gel (0-50%, EtOAc/petrol). The product (117 mg, 0.25 mmol) was dissolved in DMF (2.5 mL) and sodium azide (24 mg, 0.37 mmol) added. The reaction was heated to 65° C. for 18 h, then cooled to ambient temperature and the solvent removed in vacuo. The residue was slurried in Et2O, filtered and the filtrate evaporated in vacuo. The resulting oil was purified by column chromatography on silica gel (gradient elution, 0-75%, EtOAc/petrol), to give the title compound (81 mg, 44%) as a colourless oil. 1H NMR (Me-d3-OD): 8.14 (1H, d), 7.21 (1H, d), 7.09 (1H, dd), 4.26-4.15 (1H, m), 4.10-3.97 (3H, m), 3.76-3.46 (3H, m), 3.46-3.36 (1H, m), 3.05-2.91 (1H, m), 2.85 (1H, dd), 2.70 (1H, dd), 1.50 (9H, s), 1.38 (6H, s), 1.24 (3H, d).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].C(=O)(O)[O-].[Na+].Br[C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1>CN(C=O)C.CCOC(C)=O.O>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Temperature: 50 °C
Yield: 49.1 %

Procedure:
4-Bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (intermediate 57, 0.41 g, 1.27 mmol), sodium bicarbonate (0.42 g, 1.78 mmol) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (0.30 g, 1.27 mmol) were combined in DMF (5 ml) under nitrogen and heated at 50° C. for 18 h. The mixture was cooled to room temperature and diluted with EtOAc (75 ml) and water (10 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by flash chromatography (MeOH/DCM, 10%) provided 275 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-L-tyrosine (447 mg) prepared in Preparation 7 (1), N-(3-bromopropyl)phthalimide (644 mg) and potassium tert-butoxide (268 mg) in dimethyl sulfoxide (7 ml) was stirred for 6 hours at room temperature. The reaction mixture was diluted with water, and extracted with diethyl ether. The extract was washed with water and brine, dried, and evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-phthalimidopropyl)-L-tyrosine quantitatively as oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCOCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnn1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1cccnn1)c1ccc(F)cc1F
Yield: 29.1 %

Procedure:
Treatment of 3-methylpyridazine (4.70 g) with lithium diisopropylamide (0.05 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (8.60 g) according to the method of Example 11(i) gave the title compound, (3.40 g), m.p. 115.5°-117.5° (from ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])=[O:19])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.17 g, 42.34 mmol), K2CO3 (5.85 g) and acetone (50 ml) was added ethyl bromoacetate (5.2 ml). The reaction mixture was stirred at room temperature overnight, additional K2CO3 (1 equivalent) was added, the mixture was stirred for one hour, then additional ethyl bromoacetate (0.5 equivalents) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, water was added to the filtrate and the solvent was removed. The residue was dissolved in ether, extracted with 1M NaOH (2×100 ml), and the ether layer was dried over MgSO4 and stripped to afford, as a liquid, 7.89 g of 3-(ethoxycarbonylmethoxy)benzaldehyde.
Reaction SMILES: [C:1]([OH:13])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CN(C=O)C.ClCCl>[CH:25]1[C:24]([CH2:23][CH2:22][NH:21][C:1](/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)=[O:13])=[CH:29][CH:28]=[C:27]([OH:30])[CH:26]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of caffeic acid (300 mg; 1.66 mmol) and of triethylamine (1.5 eq; 2.49 mmol) in DMF (3.5 mL) is cooled to 4° C. using an ice bath. An amine, tyramine (1 eq; 1.66 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 1 eq; 1.66 mmol) in dichloromethane (3.5 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 30 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3×75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product is obtained in the form of a white precipitate after purification by chromatography on a column of silica gel.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O1CCCCC1[N:25]1[CH:33]=[C:32]2[C:27]([CH:28]=[C:29]([C:35]3[CH:40]=[CH:39][C:38]([O:41]C4CCCCO4)=[CH:37][CH:36]=3)[CH:30]=[C:31]2[NH2:34])=[N:26]1.[OH-].[Na+]>C(Cl)Cl>[OH:41][C:38]1[CH:37]=[CH:36][C:35]([C:29]2[CH:28]=[C:27]3[C:32]([CH:33]=[N:25][NH:26]3)=[C:31]([NH:34][C:16]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:17])[CH:30]=2)=[CH:40][CH:39]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)C1CCCCC1
Reaction time: 1 h

Procedure:
DIPEA (82 mg, 0.635 mmol) and cyclohexanecarbonyl chloride (37 mg, 0.254 mmol) were added to 2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) in DCM (1 ml) and the reaction was stirred for 1 h. 2 M Sodium hydroxide (aq) (2 ml) was added and the reaction stirred for 1 h. The organic layer was passed through a hydrophobic frit and the aqueous layer was extracted with DCM. The organic layers were combined and the solvent removed under a stream of nitrogen. The residue was dissolved in MeOH (2 ml), 4 M HCl in 1,4-dioxane (2 ml) was added and the reaction was stirred at RT for 1 h. The solvent was removed under a stream of nitrogen. The residue was purified by MDAP using the following method:
Reaction SMILES: [CH3:1]I.[Mg].[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=[CH:15][N+:16]([O-:18])=[O:17].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:1])[CH2:15][N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])C=Cc1c[nH]c2ccc(Br)cc12
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C[N+](=O)[O-])c1c[nH]c2ccc(Br)cc12
Reaction time: 12 h
Yield: 49.5 %

Procedure:
Methyl iodide (35.5 g) was added to a stirred suspension of magnesium (4.8 g) in dry ether (100 ml) over a period of 10 min. To the grey solution was added a solution of 5-bromo-3-(2-nitroethenyl)-1H-indole (13.4 g) in dry tetrahydrofuran (250 ml) over a period of 11/2 h. The resulting mass was stirred vigorously for 12 h, followed by the careful addition of saturated ammonium chloride (250 ml). After separation of the organic phase, the aqueous phase was extracted with ether (500 ml). The combined organic extracts were successively washed with 5% sodium sulphite solution (500 ml) and water (500 ml). Evaporation of the dried (MgSO4) ethereal phase gave a brown oil which was chromatographed on Kieselgel 60 using diethyl ether as eluant to give the title compound as a yellow gum (7.03 g) T.L.C. silica/diethyl ether Rf 0.5.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.[ClH:20].[N:21]1([C:28](=[NH:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+]>C(O)C.O>[ClH:20].[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:30]=1
Reactant: N=C(N)N1CCCCCC1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1occc1-c1nc(N2CCCCCC2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (205 mg, 0.8 mmol) and hexahydro-1H-azepine-1-carboximidamide hydrochloride (213 mg, 1.200 mmol) in ethanol (4 ml) was stirred at room temperature. Potassium tert-butoxide (180 mg, 1.600 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The product was dissolved in a mixture of dichloromethane (2 ml) and methanol (0.5 ml) and hydrogen chloride (1M in ether, 0.5 ml) was added and the solvent was evaporated. The residue was co-evaporated with ether and triturated with ether. The solid was collected and dried to give the title compound (67 mg, 23%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.74 (2H, d), 8.54 (1H, s), 8.12-8.10 (1H, m), 7.65-7.55 (2H, m), 7.43 (1H, d), 5.74 (1H, d), 3.84-3.80 (4H, m), 2.41 (3H, s), 1.85-1.70 (4H, m), 1.60-1.48 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.[C:16]1([NH:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:19]2[CH:20]=[CH:21][C:16]([NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cccnc1
Reactant: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccc(Cl)cc2)c2cccnc2)cc1
Yield: 100 %

Procedure:
A mixture of α-(4-chlorophenyl)-3-pyridinemethanol (0.364mol) and N-phenyl acetamide (0.364 mol) in HOAc (360 ml) and H2SO4 36N (38.6 ml) was stirred and refluxed for 6 days. The solvent was evaporated, yielding 122.6 g (±)-N-[4-[(4-chloro-phenyl)(3-pyridinyl)methyl]phenyl]acetamide (compound 673).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[C:17]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][OH:1])(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: OCCC1CCCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CCCCC1CCO
Temperature: 20 °C

Procedure:
65 g (0.5 mol) of 2-(2-hydroxyethyl)-piperidine and 90 ml of triethylamine (0.64 mol) are dissolved in 1 liter of tetrahydrofuran, and 80 ml (0.67 mol) of valeryl chloride are added at -20° C. The mixture is warmed at 20° C. for one day and the solvent is then largely removed on a rotary evaporator; the residue is taken up in methylene chloride, the mixture is washed with 1N NaOH solution, the organic phase is dried and the solvent is removed by distillation on a rotary evaporator. In order to remove impurities of the bis-acylated compound, the product is taken up in 200 ml of ethanol and the mixture is warmed at 50° C. with 200 ml of 1N sodium hydroxide solution for one hour. It is evaporated on a rotary evaporator again, the residue is extracted with CH2Cl2 /H2O, the organic phase is dried and evaporated on a rotary evaporator and the residue is distilled in a bulb tube oven (boiling point0.2 =165° C).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:29]
Reactant: CC1(C)OC(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (10.0 g, 45.5 mmol) and Cs2CO3 (23.5 g, 68.25 mmol) in DMF (60 mL) was added ethyl α-bromoacetate (11.6 g, 68.25 mmol). The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate, washed with water, dried over Na2SO4. After filtration and evaporation, the residue was dried under high vacuum to provide [4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethyl ester (12.52 g, 90% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])=O)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[O:14][C:13](=[O:15])[C:12]([CH:16]([CH3:18])[CH3:17])([CH3:19])[N:11]=2)[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C(=O)NC(C)(C(=O)O)C(C)C)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
3.7 g (12.5 mmol) of 2-[2-(4-chlorophenyl)-propanoylamino]-2,3-dimethylbutanoic acid was suspended in 50 ml of toluene. Thereto was added 2 g (19.6 mmol) of acetic anhydride. The mixture was refluxed with heating, to give rise to a reaction. The reaction was complete in 20 minutes. The reaction mixture was cooled to room temperature. 50 ml of water was added and phase separation was allowed to take place. The separated organic layer was washed with 30 ml of water and 30 ml of a saturated aqueous sodium bicarbonate solution, and then concentrated to obtain 3.2 g (yield=97%) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[NH:24]1[CH:28]=[CH:27][C:26](B(O)O)=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:28]4[CH:27]=[CH:26][NH:25][N:24]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cc[nH]n3)sc2n1
Temperature: 100 °C
Yield: 10.4 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (80 mg, 0.185 mmol), 1H-pyrazol-3-ylboronic acid (20.73 mg, 0.185 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.01 mg, 0.019 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added potassium carbonate (90 mg, 0.649 mmol) and the mixture heated to 100° C. using a microwave reactor for 30 min. The mixture was then evaporated to dryness and purified by MDAP (acidic conditions), followed by MDAP (basic conditions), to afford the title compound (8.07 mg). LCMS (A) m/z: 417 [M−1]−, Rt 0.99 min (acidic).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:46][CH:45]([NH:47][CH3:48])[CH2:44][CH:43]1[CH2:49][OH:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH:45]([N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH3:48])[CH2:44][CH:43]1[CH2:49][OH:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CNC1CC(CO)N(C(=O)OC(C)(C)C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CC(CO)N(C(=O)OC(C)(C)C)C1

Procedure:
4-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Hydroxymethyl-4-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:37][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.036 g, 0.18 mmol), 1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]-4-phenylpiperidin-4-ol (0.035 g, 0.092 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in ethanol (0.32 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product as the free base. LCMS calculated for C27H27ClN7O (M+H)+: m/z=500.2; Found: 500.1.
Reaction SMILES: IC.[CH3:3][C:4]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:17](=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH3:17][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([CH3:3])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:7][CH:8]=1
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Yield: 63.7 %

Procedure:
Iodomethane (0.12 mL, 1.3 mmol) was added to a mixture of 4-(2-methyl -2-nitropropyl)phenol (300 mg, 1.5 mmol) and potassium carbonate (425 mg, 3.1 mmol) in tetrahydrofuran (20 mL) and N,N-dimethylformamide (1 mL). After refluxing overnight, the mixture was cooled and concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated to provide crude 1-methoxy-4-(2-methyl-2-nitropropyl)benzene (200 mg, 62% yield) as yellow oil which was used directly in the next step.