Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(NC(C)C)(C)C.[I-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][C:20]2[C:25](=[O:26])[N:24]3[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:23]3=[N:22][C:21]=2[CH3:32])[CH2:15][CH:16]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (5.5 g, 0.025 mol), 3-(2-chloroethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (7.2 g, 0.030 mol), diisopropylamine (5 ml) and potassium iodide (1 g) in acetonitrile (100 ml) was heated under reflux for 24 h. After cooling the precipitate was collected and washed with acetonitrile (20 ml), isopropyl alcohol (3×20 ml) and petroleum ether (25 ml) respectively. Yield 7.13 g (67%) of a pale yellow solid. M.p.: 229-230° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:27])[CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C=O)C>[C:7]([CH2:9][C:10]([NH:27][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26])=[O:12])#[N:8]
Reactant: CCCC(N)c1ccc(OCOC)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CC#N)c1ccc(OCOC)cc1
Temperature: 25 °C
Yield: 102.4 %

Procedure:
Oxalyl chloride (1.03 g, 8.15 mmol) was added drop-wise at ice bath temperature under nitrogen to a stirred solution of cyanoacetic acid (0.67 g, 7.9 mmol) in tetrahydrofuran (15 mL) to which 1-2 drops of DMF had been added. The mixture was stirred for an hour, then added slowly in one portion to a stirred solution of 1-(4-(methoxymethoxy)phenyl)butan-1-amine (1.1 g, 5.3 mmol) in THF (15 mL) at ice bath temperature under nitrogen. The mixture was allowed to warm gradually to room temperature and after 20 hours was stirred into 50 mL of saturated aq sodium bicarbonate and extracted 3× with dichloromethane. The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo, leaving 1.5 g of dark violet syrup. The product was flash chromatographed on a column (50×70 mm) of silica gel (43-60 μm) eluting with Hxa/EtOAc 1:1 to afford 1.0 g (69%) of clear, dark oil; homogeneous by TLC.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[OH-].[Na+].CN([CH:21]=[O:22])C>>[CH3:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH:21]=[O:22])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c2ccccc2c1C=O
Reaction time: 2 h
Yield: 89 %

Procedure:
To a dried 300 mL two-neck round bottom flask under argon at 0° C., N,N-dimethylformamide (3 mL) was added, followed by POCl3 (1.05 mL, 11.3 mmol). After stirring for ten minutes, 2-methylindole (1.23 g, 9.37 mmol) dissolved in DMF (6 mL) was added dropwise via an addition funnel under argon. After two hours, 1 N NaOH (70 mL) was added slowly, upon which a white precipitate formed. The solid was filtered and dried under vacuum, yielding 1.32 g (89%) of white solid. 1H NMR (600 MHz, d6-DMSO): δ 11.998 (s, 1H, N—H), 10.050 (s, 1H, CHO), 8.044-8.032 (d, J=7.2, 1H, indole-4H), 7.388-7.375 (d, J=7.8, 1H, indole-7H), 7.183-7.135 (m, 2H, indole-5,6H), 2.679 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 184.3, 148.6, 135.4, 125.6, 122.7, 121.9, 120.0, 113.7, 111.4, 11.5. Melting Point: 195-200° C. TLC (ethyl acetate:hexanes 4:1) Rf=0.39. Elemental analysis calculated for C10H9NO: C, 75.45; H, 5.70; N, 8.80. found: C, 75.23; H, 5.70; N, 8.93.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[OH:32].[C:33]([NH:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([N:48]=[N:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[C:45]=2[OH:47])[C:40]([S:58](Cl)(=[O:60])=[O:59])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([N:48]=[N:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[C:45]=2[OH:47])[C:40]([S:58]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:12][S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[OH:32])(=[O:59])=[O:60])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)c(N)c12
Reactant: COc1ccccc1N=Nc1ccc2c(S(=O)(=O)Cl)ccc(NC(C)=O)c2c1O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)c(NS(=O)(=O)c3ccc(NC(C)=O)c4c(O)c(N=Nc5ccccc5OC)ccc34)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 0.85 g (0.0018 mole) crude 1-amino-8-hexadecanesulfonamido-2-naphthol in 16 ml pyridine at 0° C was added 0.81 g (0.0018 mole) 4-acetamido-5-hydroxy-6-(o-methoxyphenylazo)naphthalene-1-sulfonyl chloride. The mixture was stirred overnight at room temperature, then poured in ice water containing 18 ml concentrated hydrochloric acid. The product was dried and triturated first with hot 1:1 dioxaneisopropyl alcohol and then with hot methanol to give 0.85 g of product, m.p. 177°-180° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([OH:12])[CH2:10][C:9]2[C:8]([O:13]C(C)(C)C(OCC)=O)=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:22](=[C:3]1[CH:2]([OH:1])[CH:11]([OH:12])[CH2:10][C:9]2[C:8]([OH:13])=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1C[C@H](O)[C@H](O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC=C1c2cccc(O)c2CC(O)C1O

Procedure:
A solution of 3.6 g (0.02 moles) of the triol of Example 1 in 50 ml. of benzene, and 1.5 g of butanal in the presence of 0.1 g p-toluene sulfonic acid are mixed together and stirred for several hrs. Water is removed by azeotropic distillation and the residue is taken to dryness to yield 06, 07 -butylidene - 5,6,7,8-tetrahydro-1,6,7-naphthalene triol.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: Cc1cccc(CO)c1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(C)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
This compound was prepared by reacting 333 mg (1.295 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate with 0.31 mL (2.59 mmol) of 3-methylphenylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)tributylphosphorane (CMBP). The reaction mixture is stirred at 110° C. for 15 hours and then concentrated to dryness. The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate, to give 376 mg of the expected product in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[NH2:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:27][CH:28]=O.O>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]3[CH:27]=[CH:28][N:25]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1nc(N)n2-c1ccc(OCc2ccccc2)cc1
Reactant: O=CCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3-[4-(benzyloxy)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine (4.96 g) and 6.1 M aqueous chloroacetoaldehyde solution (4.92 ml) in DMA (50 ml) was stirred at 100° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from hexane/THF to give the title compound (1.39 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:14]1[CH2:15][CH:12]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34](=[O:46])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:29][CH2:28]4)=[CH:3]2)[CH2:13]1
Reactant: CN1CC(n2cc(Br)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c3c(N)ncnc32)C1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
To 5-bromo-7-(1-methyl-3-azetidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.227 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (137 mg, 0.318 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes and Pd(Ph3P)4 (26.2 mg, 0.023 mmol) was added and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 20% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the product was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 7-(1-methyl-3-azetidinyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15 mg, 0.030 mmol, 13.06% yield) as a white solid. LC/MS (ES) m/z=507.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.14 (d, J=8.08 Hz, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 4H), 7.38 (s, 1H), 7.27 (d, J=8.08 Hz, 1H), 6.16 (br. s., 2H), 5.41 (quin, J=7.20 Hz, 1H), 4.28 (t, J=8.34 Hz, 2H), 4.06-4.13 (m, 2H), 4.04 (s, 2H), 3.90-3.99 (m, 2H), 3.24-3.29 (m, 2H), 2.65 (br. s., 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)Br
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Product: CC(C)Oc1c(Br)cc(Br)c2cccnc12
Yield: 97 %

Procedure:
Reaction of 5,7-dibromo-quinolin-8-ol with 2-bromopropane following the method described in Example 8 gave 5,7-dibromo-8-isopropoxy-quinoline 6 (97%): 1H NMR (CDCl3): δ 8.94 (dd, J=1.5 and 4.2, 1 H), 8.48 (dd, J=1.5 and 8.4, 1H), 8.00 (s, 1 H), 7.52 (dd, J=4.2 and 8.4, 1 H), 5.22 (m, 1 H), 1.43 (d, J=6.1, 6 H); mass spectrum: m/z 344, 346, 348 (M++1, 50, 100 and 50%, respectively). Reaction of 6 with aryl boronic acids, and cleavage of the isopropoxy group following the method outlined in Example 8 gave compounds L1 and L2 (data in Table 4).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][N:13]([CH3:18])[CH2:14]N(C)C>CC(O)=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][N:13]([CH3:18])[CH3:14])=[CH:5][NH:6]2
Reactant: Cc1cc(C)c2cc[nH]c2c1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(CN(C)C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,6-dimethyl-1H-indole (Cho et al., Tetrahedron, 2001, 57, 3321-3330) (93.0 mg, 0.640 mmol) and N,N,N′,N′-tetramethylmethanediamine (98.0 mg, 0.961 mmol) in AcOH (3 mL) was stirred at ambient temperature for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(chloromethyl)-4-methoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.72 min.; [M+H]+: 356.26 g/mol.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][OH:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>ClCCl>[C:25]([O:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCC(CO)NC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC=CCCCCCCCC(=O)OCC(CCCCCCCCCC)NC(C)=O
Yield: 82.8 %

Procedure:
To a solution of 2.43 g of 2-ethanoylaminododecanol, 3 g of triethylamine in 50 ml of dichloromethane is added 3.2 g of oleoyl chloride. The reaction mixture is worked up as under Example 9 to give 4.2 g of product.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[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].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl
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: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (116 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol) [prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 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 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.19 mmol, 42% yield) as a yellow oil: LCMS (ES) m/e 591, 593 (M, M+2)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH2:7][C:8]([N:24]2[CH2:25][CH:26]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20][S:21][CH:22]3[CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1.15 cm3 of phenylacetyl chloride in 25 cm3 of dichloromethane is added over 5 minutes to a solution, cooled to 0° C., of 2.63 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 2.42 cm3 of triethylamine in 25 cm3 of dichloromethane. After stirring for one hour at 0° C. and one hour at 20° C. 20 cm3 of dichloromethane are added. The reaction mixture is washed twice with 100 cm3 of distilled water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 125 cm3. Fractions 19 to 26 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.87 g of (4aRS,7aRS)-6-phenylacetyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of a white solid; melting point 210° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccc(Cl)cc5)c[nH]4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 125.7 %

Procedure:
A mixture of 4-(2-amino-6-{2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-4-pyrimidinyl)-2-fluorobenzonitrile (155 mg, 0.326 mmol) and hydrazine (1.033 mL, 32.6 mmol) in ethanol (4 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The solvent was evaporated to get 200 mg of residue, which was purified by preparative HPLC to afford the title compound (19 mg) as a yellow powder. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.32-3.08 (m, 2H), 3.72 (t, J=11.2 Hz, 1H), 4.06-4.01 (m, 1H), 4.31-4.34 (m, 1H), 4.61 (d, J=14.0 Hz, 1H), 4.72 (bs, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.75 (s, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.76-7.46 (m, 3H), 7.81 (d, J=8.4 Hz 2H), 7.99 (s, 1H), 11.53 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)CCCC>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][NH:8]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccccc1OCCCCl
Solvent: CCCCCO
Product: ClCCCOc1ccccc1Nc1nc(Cl)nc2[nH]cnc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2,6-Dichloropurine (10 mmol) and 2-(3-Chloro-propoxy)-phenylamine (˜20 mmol) are dissolved in 1-pentanol and heated up to 70° C. and the mixture is stirred at this temperature for 5 hours. While cooling down to R the product precipitated. The solid material was filtered off and washed with 1-pentanol and diethyl ether. A solid powder with mp. 205° C., Rf=0.42 (CH2Cl2/MeOH=10:1) is obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:15]([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[OH:16])[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[N+:25]([O-])([OH:27])=[O:26]>O>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:15]([C:21]([F:24])([F:22])[F:23])([C:17]([F:18])([F:19])[F:20])[OH:16])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[CH:13][CH:14]=1)[CH3:1]
Reactant: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of 4-(1-methylethyl)-5-phenyl-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanol (1.75 g) in 40 ml of water was added 2.5 ml of concentrated nitric acid in a dropwise manner. The mixture was stirred for 30 minutes, and the nitrate salt, 1.51 g) was filtered off. The solid in 5 ml of concentrated sulfuric acid was heated at reflux for 2 hours. The reaction mixture was poured into 50 ml of ice-water. The mixture was basified to a pH of 8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to afford a yellow solid which was purified by flash chromatography on silica gel (85:15 hexane/ethyl acetate) to afford (0.98 g, 50%) of the title compound as a pale yellow solid, m.p. 157°-160° C.