Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])(=O)=O.[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:15]([CH2:16][CH2:17][OH:18])[CH3:14]
Reactant: CNCCO
Reactant: CS(=O)(=O)OCc1ccccc1F
Product: CN(CCO)Cc1ccccc1F
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A mix of 2-Fluorobenzyl methanesulfonate (Step A, 5 g, 24.5 mmol) and 2-(Methylamino)-ethanol (18.4 g, 244.9 mmol) was heated under argon at 120° C. with stirring for 7 hours. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel column (chloroform:methanol, 90:10 spiked with triethylamine) to provide the title compound.
Reaction SMILES: [H-].[Na+].[O-]CC.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].[C:22]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:37])[CH2:35]Br)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([CH2:35][C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:29][CH:30]=1)=[O:37])[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(-c2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (15 mmol) is added to anhydrous ethanol (50 mL). To this resulting sodium ethoxide solution is added 2-acetylaminomalonic acid diethyl ester (15 mmol) in one portion. The resulting mixture is stirred at room temperature for 30 min. A solution of 4′-phenyl-2-bromoacetophenone (10 mmol) in ethanol (10 mL) is then added and the resulting mixture is stirred at room temperature for 12 h. After concentrating under reduced pressure, the residue is dissolved in EtOAc and water. The organic phase is washed with brine and dried over Na2SO4. After removal of the solvent, the crude material is purified by column chromatography using EtOAc/hexane (1/3) giving the desired product as white solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.45 (m, 3H), 7.13 (s, 1H), 4.28 (m, 6H), 1.98 (s, 2H), 1.26 (t, J=7.1 Hz, 6H); MS: (ES+): 412.2 (M+1)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:25]([N:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:4][CH:3]=[N:2]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Oc1ccccc1-c1ccn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1ccnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et al., J. Am. Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1.60 g), triethylamine (40.0 mmol, 5.6 ml), and acetonitrile (55 ml) is cooled in an ice bath under N2 and treated dropwise with chlorotrimethylsilane (12.0 mmol, 1.52 ml). After the addition is complete, the cold bath is removed and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is then treated with trityl chloride (10.0 mmol, 2.78 g) and stirred at ambient temperature overnight, followed by refluxing for 1 hour. The reaction mixture is concentrated, treated with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3×50 ml). The extracts are dried over magnesium sulfate and concentrated to a viscous oil. The oil is crystallized from 20% ethyl acetate/hexane to give 1.72 g of N-trityl-2-(pyrazol-5-yl)phenol.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)(=[O:31])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 51 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.271 g, 1.0 mmol) in pyridine (5 ml) was added 2-naphthalene sulfonyl chloride (0.269 g, 1.18 mmol). The mixture was stirred for 3 h, then water (25 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to give the title compound (0.231 g, 51%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.92-3.07 (2H, m), 3.29 (2H, dd, J=3.9, 10.2 Hz), 3.45 (2H, dd, J=3.9, 12.3 Hz), 3.59 (2H, dd, J=7.2, 10.2 Hz), 4.35 (2H, q, J=7.2 Hz), 7.58-7.75 (2H, m), 7.82 (1H, dd, J=1.8, 8.7 Hz), 7.90-8.05 (2H, m), 8.40 (1H, s), 8.77 (2H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=O)[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)(O)[O-].[Na+].O>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[N:35][OH:36])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (10.5 mg, 17.7 μmol) prepared in Process B was dissolved in ethanol (1.5 ml). Hydroxylamine hydrochloride (40 mg, 0.57 mmol) and saturated aqueous solution of sodium bicarbonate (0.3 ml) were added thereto, and the mixture was stirred at room temperature for two hours. Water (5 ml) was added to the reaction solution, which was extracted with ethyl acetate (6 ml×3). The organic layers were combined, washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel-column chromatography (Presep (r) silica gel, 10 g, Wako Pure Chemical Industries, Ltd., n-hexane/ethyl acetate (4:1)) to give N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-(hydroxyiminomethyl)-benzamide (5.0 mg, 46%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)(O)[O-].[Na+].O>CCOCC>[CH:2]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1ccsc1C1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)CSc1ccsc1C=O
Reaction time: 1 h
Yield: 87 %

Procedure:
Methyl-3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) (117.63 g, 0.515 mole) was dissolved in actone (500 mL), and p-tolunesulfonic acid hydrate (1.30 g., 6.83 mmole) was added and stirred over 1 hour. A saturated solution of sodium bicarbonate (20 mL) was added followed by water (250 mL). The acetone was evaporated leaving a tacky solid in water. This tacky solid was dissolved in ether and washed with water four times, dried (MgSO4), filtered and the solvent evaporated in vacuo to leave 96.91 g of crude methyl 3-(2-formylthiophen-3-yl)-3-thiapropionate (5) which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=2)[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)=[C:4]([CH3:15])[CH:5]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OC4CCCCO4)cc3C)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of methyl 3-[4-[[2′,6′-dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy]phenyl]propanoate (2.92 g, 6.15 mmol), p-toluenesulfonic acid monohydrate (0.12 g, 0.62 mmol) and methanol (60 mL) was stirred at room temperature for 2 hrs., and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (2.12 g, yield 88%) as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][CH2:29][CH2:30][C:31]2[N:36]=[C:35]3[CH2:37][O:38][C:39](=O)[C:34]3=[CH:33][CH:32]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:39]1[C:34]2[C:35](=[N:36][C:31]([CH2:30][CH2:29][CH2:28][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[CH2:37][O:38]1
Reactant: O=C1OCc2nc(CCCN3CCOCC3)ccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (190 mg, 1.26 mmol.) in THF (1 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (4 mL of a 1M in THF, 4 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-(3-Morpholin-4-yl-propyl)-7H-furo[3,4-b]pyridin-5-one (220 mg, 0.84 mmol) in THF (15 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4.5 h and then poured into an aqueous 10% HCl solution (50 mL). The resulting solution is stirred for 70 h at room temperature. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, and Et2O and dried under vacuum give the title compound (110 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([C:29]3[N:34]=[CH:33][C:32]([C:35]4[CH:36]=[N:37][NH:38][CH:39]=4)=[CH:31][N:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:37]2[CH:36]=[C:35]([C:32]3[CH:31]=[N:30][C:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:21]5[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=5)[CH:24]=4)=[N:34][CH:33]=3)[CH:39]=[N:38]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 170.1 %

Procedure:
4-Methanesulfonyloxy-cyclohexanecarboxylic acid ethyl ester (AOKChem Co., Ltd; 689 mg; 2.75 mmol; 1.04 eq.) in DMF (5 mL) was added in one portion to a suspension of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 104 mg; 0.34 mmol; 1.0 eq.) and cesium carbonate (2.35 g; 7.21 mmol; 2.7 eq.) in DMF (10 mL). The reaction mixture was heated in MW at 120° C. for 35 min. It was then poured into water and filtered. The resulting solid was triturated with ACN to give the title compound as a yellow solid (264 mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.57-8.46 (m, 2H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.32-3.99 (m, 3H), 3.89 (s, 3H), 2.48-2.34 (m, 1H), 2.23-1.48 (m, 8H), 1.27-1.14 (m, 3H). MS (ESI+): 457.3.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:30]1[CH:29]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
Lithium hydroxide monohydrate (0.022 g, 0.52 mmol) was added to a stirred solution of {4-[4-(3-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.063 g, 0.12 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 51%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H) 8.19 (d, J=8.20 Hz, 2 H) 8.13 (t, J=2.10 Hz, 1 H) 8.05 (d, J=7.60 Hz, 1 H) 8.00 (dd, J=8.90, 5.80 Hz, 1 H) 7.91 (s, 1 H) 7.84 (d, J=7.60 Hz, 1 H) 7.72 (t, J=8.10 Hz, 1 H) 7.54 (d, J=8.10 Hz, 2 H) 7.38 (td, J=8.30, 2.60 Hz, 1 H) 6.64 (dd, J=10.90, 2.40 Hz, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H). MS calcd. for C25H18ClFO4S [(M−H)−] 467, obsd. 467.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>O1CCCC1>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCOc2cc(O)ccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)OCCC2=O
Temperature: 70 °C
Yield: 72.2 %

Procedure:
7-Hydroxy-2,3-dihydrochromen-4-one (4.47 g, 27.2 mmol) was diluted with tetrahydrofuran (40 mL) followed by the addition of K2CO3 (5.64 g, 40.8 mmol) and MeI (2.55 mL, 40.8 mmol). The reaction was heated at 70° C. for 5 hours. The reaction was allowed to cool and loaded onto a Biotage 40M cartridge running a gradient 5% ethyl acetate/hexanes to 75% to yield the title compound (3.5 g, 72.1% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:35]1[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([N:31]([CH:40]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35]2)[CH3:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:17](=[O:23])[NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1C=CCCC1
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C1C=CCCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Example 35) (1.0 mmol) was dissolved in THF (10 mL) and treated with 3-bromocyclohexene (1.5 mmol) and diisopropylethylamine (3 mmol). The reaction was stirred at 50° C. for 18 hours. Then the reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was chromatographed on silica gel eluting with a gradient of 10-30% acetone/CH2Cl2 to give the title compound with the yields of 50%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH3:12])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (587 mg, 2.78 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (2.5 ml) and TEA (400 μl, 2.87 mmol) was added. To this solution, 2-methoxyaniline (340 mg, 2.76 mmol) in 3 ml DCM was added dropwise and the mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (10% to 40%, hexane-ethyl acetate) to obtain 630 mg (77% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:42])[CH:17]([C:24]2[N:25]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[N:26]=[C:27]3[C:32]=2[CH:31]=[C:30]([F:33])[C:29]([F:34])=[CH:28]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11]([F:43])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C1COCC1.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:44])=[O:3])=[CH:10][C:11]=3[F:43])=[O:42])=[C:32]3[C:27]([CH:28]=[C:29]([F:34])[C:30]([F:33])=[CH:31]3)=[N:26]2)=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 7.2, [rac]-2-(4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as red solid. MS: m/e=600.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.FC(F)(F)S(O)(=O)=O.[I:17]N1C(=O)CCC1=O.[OH-].[Na+]>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ncn1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncnc(Cl)c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-chloropyrimidin-4-amine (5.29 g, 40.8 mmol) and trifluoro-methane sulfonic acid (40 mL, 452 mmol) was added N-iodosuccinimide (9.19 g, 40.8 mmol). The mixture was stirred for 3 h at rt. The mixture was poured into 50 mL of ice containing 15 g of NaOH with stirring for 10 min. The resulting precipitate was filtered washed with water, triturated in DCM and collected by filtration to give 6-chloro-5-iodopyrimidin-4-amine: 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H); LC-MS (ESI) m/z 255.9 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:30]>[Pd].CO>[ClH:30].[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 25 °C

Procedure:
150 g of (3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone, 1500 cm3 of methanol and 450 cm3 of 1N hydrochloric acid are added to 15 g of 10% palladium on charcoal; the reaction mixture is hydrogenated, with stirring, at room temperature and at atmospheric pressure. The theoretical volume of hydrogen was absorbed after 5 hours of reaction; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized from 200 cm3 of ethanol; the crystals obtained are drained, washed with 50 cm3 of ethanol and dried. 110 g of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride are obtained; melting point 270° C., with decomposition.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.[C:16]([NH:19][CH2:20][CH2:21][NH2:22])(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:22]([CH2:21][CH2:20][NH:19][C:16](=[O:18])[CH3:17])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(=O)NCCN
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)C2
Yield: 15.1 %

Procedure:
A solution of 4.5 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 2.3 g of N-acetylethylenediamine in 100 ml of toluene was boiled under reflux for 10 minutes. The reaction mixture was evaporated in a vacuum, taken up in dichloromethane, dried with magnesium sulfate and again evaporated. After purification on silica gel (ethyl acetate), 0.9 g (15%) of N-[2-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-ethyl]-acetamide was obtained as a yellowish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)c1ccccc1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 14.8 %

Procedure:
4-nitrophthalic anhydride (0.5 g, 0.0026 mol) and o-aminobenzoic acid (0.36 g, 0.0026 mol) were refluxed as above for four days. The clear solution was purified as per 120 with an additional final crystallisation from acetone/H2O to yield 0.12 g (15%) 147 as a very pale dull yellow powder: mp=242–243° C.; Rf 0.80 (A): Rf 0.88 (C): Rf 0.49 (D): IR (cm−1): 2725–3100 (OH), 3071 (C═CH), 2646 (C—H), 1786 (C═O), 1730 (C═O), 1693 (C═O), 1620 (C═C), 1601 (C═C), 1538 (N═O), 1491 (C═C), 1452 (C═C), 1383 (C—O), 1345 (N═O), 1123 (C—O), 723 (C═CH); MS m/z (rel intensity) 311 (33), 267 (76), 241 (54), 136 (100).