Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=2)=[O:38])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:29]=[CH:28][C:27]([C:37]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=3)=[O:38])=[CH:26][C:25]=2[Cl:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1nc(C(=O)c2ccc(OCCCCO)c(Cl)c2)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nc(C(=O)c2ccc(OCCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
Triethylamine (830 μL), trimethylamine hydrochloride (188 mg) and 4-methylbenzenesulfonyl chloride (555 mg) were sequentially added to a solution of [3-chloro-4-(4-hydroxybutoxy)phenyl](5-chloro-6-methoxypyridin-2-yl)methanone obtained in Reference Example 1-34(1) (360 mg) in chloroform (8 mL) under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. Triethylamine (150 μL) and 4-methylbenzenesulfonyl chloride (185 mg) were sequentially added under ice-cooling, and the mixture was stirred at room temperature for further 1.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (357 mg, 70%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>CC#N>[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: CC#N
Product: CC(C)Oc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1
Temperature: 160 °C
Yield: 59.2 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.2 g, 0.7 mmol), 4-isopropoxyaniline (0.106 g, 0.7 mmol) and TEA (0.071 g, 0.7 mmol) was dissolved in dry MeCN (3 ml). The reaction mixture was heated at 160° C. for 30 min in a microwave reactor. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 70:30 mixture of heptane:EtOAc as eluant to give the title compound (0.166 g, 59%). 1H NMR (500 MHz, CDCl3): δ 7.21-7.15 (m, 1H), 7.13-7.09 (m, 4H), 7.06 (brs, 1H), 6.65-6.59 (m, 2H), 6.53-6.48 (m, 2H), 4.48 (hep, 1H), 4.35 (hep, 1H), 1.63 (d, 6H), 1.23 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 159.0, 155.5, 131.6, 129.5, 128.9, 128.1, 125.0, 124.1, 124.0, 116.0, 109.7, 70.4, 47.8, 21.9, 20.4.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([O:23]C)=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH:6]=[CH2:7].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH:42][C:21]([C:18]3[CH:19]=[N:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][N:8]([CH2:5][CH:6]=[CH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)=[O:23])[NH:40][N:41]=2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: C=CCN1CCCN(c2ncc(C(=O)OC)cn2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C=CCN1CCCN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
Trimethylaluminium (1.35 ml, 2.70 mmol) was added dropwise to a stirred suspension of methyl 2-(4-prop-2-enyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (300 mg, 1.09 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (268 mg, 1.09 mmol) in toluene (5.43 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (220 mg, 41%) as a cream solid.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>O1CCOCC1.[Cu](I)I.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>[O:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[Si](C)(C)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
224 mg (1.2 mmol) of copper iodide, 309 mg (3 mmol) of triethylamine and 165 mg (0.23 mmol) of dichlorobis(triphenylphosphine)-palladium (11) are added to a suspension of 898 mg (2.35 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 30 ml of anhydrous dioxan then this mixture is degassed under argon. After 15 minutes, 346 mg (3.52 mmol) of ethynyl-trimethyl-silane is added and the reaction mixture is heated at 100° C. for 3 hours. The raw reaction product is filtered on celite, then the filtrate is evaporated to dryness and the residue is purified on silica (eluent ethyl acetate) to give 400 mg (48%) of 4-oxo-8-trimethylsilanylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a yellow solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18](\[CH3:24])/[C:19](OCC)=[O:20]>C(Cl)Cl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:20]
Reactant: CCOC(=O)/C(C)=C/c1ccccc1F
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)/C(C)=C/c1ccccc1F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (7 g, 72 mmol) was slurried in CH2Cl2 (250 mL) and cooled to 0-5° C. A solution of trimethylaluminum (2M in toluene, 36 mL, 72 mmol) was added dropwise. The mixture was warmed to ambient temperature and stirred for 1 hr. A solution of Example 3A (5 g, 24.0 mmol) in CH2Cl2 (100 ml) was added and the solution was heated to reflux overnight. The reaction mixture was cooled in an ice bath and quenched carefully with ice cold 0.5 M HCl. The mixture was filtered through celite filter aid and extracted with CH2Cl2. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was chromatographed (SiO2, 100% hexanes to 20% ethyl acetate/hexanes) to afford the title compound (1.88 g, 35% yield) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.27-7.38 (m, 2H), 7.04-7.17 (m, 2H), 6.79 (s, 1H), 3.72 (s, 3H), 3.30 (s, 3H), 2.04 (s, 3H). MS (ESI+) 224 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:29]=3)[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCCC3)CC2)c1

Procedure:
Example 138 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.52–7.46 (m, 1H), 7.45–7.43 (m, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.17 (t, 1H, J=7.9 Hz), 7.07–7.01 (m, 2H), 6.89–6.84 (m, 1H), 5.99–5.94 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.59–2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41–2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.04–1.96 (m, 2H), 1.93–1.85 (m, 2H), 1.82–1.71 (m, 4H), 1.64–1.50 (m, 8H), 1.17 (d, 6H, J=6.5 Hz); ESMS m/e: 542.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-])=O)=[C:16]([CH2:18][C:19](O)=[O:20])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO.C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:22][C:19](=[O:20])[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(OCCOCc3ccccc3)ccc2N1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-acetic acid (0.58 g, 1751 mmol), 5% palladium on carbon (0.05 g) and triethylamine (0.37 ml, 2.66 mmol) in methanol (35 ml) was stirred under a hydrogen atmosphere (1 atm) for 3 h. After removal of the catalyst by filtration, the filtrate was evaporated to give a yellow oil. The oil was dissolved in 10 ml of acetic acid and the solution was stirred at 80° C. under argon for 3 h. The acetic acid was removed on a rotavap. The residue was dissolved in a small amount of methylene chloride and chromatographed on silica gel eluted with 30% ethyl acetate in methylene chloride to give 5-(2-benzyloxy-ethoxy)-1,3-dihydro-indol-2-one (0.39 g, 79%) as a white solid. Analysis calculated for C17H17NO3 : C, 72.07; H, 6.05; N, 4.85. Found: C, 72.09; H, 6.01; N, 4.85.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCCN(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN(c2ccccc2)C1=O
Reaction time: 11 h

Procedure:
The product from Step C (0.551 g, 2.56 mmol) was dissolved in methanol (3 mL) and 5% aqueous sodium hydroxide added (3 mL). After 11 h, methanol was removed in vacuo, and the residue partitioned between ethyl acetate and 10% aqueous HCl. The organic layer was washed with saturated brine, and dried over MgSO4. The title compound was obtained as a white solid.
Reaction SMILES: [Br-].[CH2:2](OC1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCC.C([Li])CCC.[CH2:43]([O:45][C:46](=[O:57])[CH:47]=[C:48]([CH3:56])[CH:49]=[CH:50][CH:51]=[C:52]([CH:54]=O)[CH3:53])[CH3:44].CO>O1CCCC1.CCCCCC>[CH2:43]([O:45][C:46](=[O:57])[CH:47]=[C:48]([CH3:56])[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[CH:54]=[CH2:2])[CH3:44]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCCCCCCCCOc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: C=CC(C)=CC=CC(C)=CC(=O)OCC
Temperature: -40 °C
Yield: 119 %

Procedure:
A solution of [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (150 g) in tetrahydrofuran (1100 mL) was cooled to -50° C. to yield a fine suspension of the solid salt. To this mixture was added a solution of n-butyllithium in hexane (180 mL, a 1.6 molar) to yield a solution of the ylide. The mixture was then stirred a further15 min at -40° C., cooled to -70° and treated with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (65 g) dissolved in tetrahydrofuran (250 mL). Addition of hexane and aqueous methanol (40%) to the reaction mixture follwed by concentration of the hexane extract yielded ALL(E)-9-[2-nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (64 g, 58% yield), mp 52-53° C. This ester was then hydrolized by forming a solution of this ester (70 g) in ethanol (1000 mL). This solution was treated with aqueous potassium hydroxide (80 g in 400 mL water) and heated at reflux for 1 h. Water and aqueous mineral acid was then added and the solids were extracted into chloroform. Concentration of this organic extract and crystallization of the residue from an ethyl acetate hexane mixture yielded All(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid (38 g), mp 102-103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Yield: 154.2 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(380 mg, 1.0 mmol) was dissolved in ethanolamine(5 ml), then reacted at the same condition of Step 5 in the Example 1 to obtain 311 mg of desired compound as solid in 77% of yield.
Reaction SMILES: I[CH2:2][C:3]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4]1.[C:13]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[C:13]([O:17][C:18]([NH:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4]2)[CH2:25][CH2:26]1)=[O:27])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)C1(CI)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 120 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 1-(iodomethyl)cyclopropanecarboxylate (1.9 g 6.7 mmol, step 1 of Example 3), tert-butyl(piperidin-4-ylmethyl)carbamate (3.0 g, 14 mmol), N,N-diisopropylethylamine (5.8 mL, 34 mmol) in N,N-dimethylformamide (25 mL) was heated at 120° C. for 20 h. After cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate/toluene (1:2, 60 mL×2), washed with water (50 mL×2), brine (50 mL), dried over MgSO4, filtered and concentrated to give brown oil. The oil was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (10:1) to give 560 mg (1%) of the title compound as clear brown oil. MS (ESI) m/z: 369 (M+H)+. 1H-NMR (CDCl3) δ: 4.60 (1H, br), 3.08-2.82 (4H, m), 2.59 (2H, s), 2.10-1.90 (2H, m), 1.75-1.55 (4H, m), 1.50-1.05 (23H, m).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:25](=[CH2:26])[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: C=CC(=O)OCC
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C(=O)OCC)C(O)c1cc(-c2ccccc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and DABCO (10 mmol. 1.12 g) was added an methy/ethyl acrylate (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜5 min.) was diluted with diethyl ether (300 ml) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (316.5 g.).
Reaction SMILES: ClC1C=CC(C2(C)C(C3C=CC(Cl)=CC=3)(C)N([C:21](Cl)=[O:22])C(C3C=CC(C(F)(F)F)=CC=3OCC)=N2)=CC=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][N:50]([CH:21]=[O:22])[CH2:49][CH2:48]1)(=[O:42])=[O:43]
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CS(=O)(=O)CCCN1CCN(C=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the racemic rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone. Chiral separation of the enantiomers by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C35H40N4O4SF3Cl2 [(M+H)+] 739.2094, observed 739.2094.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][C:3]=1[CH3:15].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:18]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][C:3]=1[CH3:15])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Cc1cc(C2OCCCO2)cc(C)c1Br
Solvent: C1CCOC1
Product: C=CCc1c(C)cc(C2OCCCO2)cc1C
Temperature: 40 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The corresponding Grignard-reagent is prepared form 2-(4-bromo-3,5-dimethyl-phenyl)-[1,3]dioxane (2.5 g, 9.22 mmol) and Mg (258 mg, 10.6 mmol) in THF (50 mL). To this reagent allylbromide (1.23 g, 10.14 mmol) is added dropwise at rt. The reaction mixture becomes warm (40° C.) and it is stirred for 16 h. The reaction is quenched by adding water. The mixture is extracted with EA. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 10:1 to give 2-(4-allyl-3,5-dimethyl-phenyl)-[1,3]dioxane (1.8 g) as a colourless oil; LC-MS: tR=1.02 min, [M+1]+=233.22, 1H NMR (CDCl3): δ 7.12 (s, 2H), 5.94-5.80 (m, 1H), 5.44 s, 1H), 4.95 (dd, J=1.8, 10.0 Hz, 1H), 4.80 (dd, J=1.8, 17.0 Hz, 1H), 4.30-4.21 (m, 2H), 4.04-3.92 (m, 2H), 3.40-3.34 (m, 2H), 2.32-2.26 (m, 8H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[CH:1]1([C:7]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]5)[N:19]=[C:20]([NH2:34])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C3CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from cyclohexanecarboxylic acid (Aldrich, Cat. #101834) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=435.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+]([O-])([O-])=[O:22].[Na+]>S(=O)(=O)(O)O.O>[OH:22][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2nc(O)cc3cccnc23)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-8-(3-nitrophenyl)-1,7-naphthyridine (500 mg, 1.87 mmol; prepared according to example 1) in concentrated sulfuric acid and water (3 ml, 2:1) is added sodium nitrate (155 mg, 2.25 mmol) at 4° C. After 30 minutes, the ice bath is removed, and the mixture is warmed to 70° C. for 30 minutes. the reaction mixture is poured onto ice, and the solution is neutralized by adding sodium bicarbonate. The precipitate is filtered and washed with water affording the title compound. mp 262-265° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[C:28]2[N:39]=[CH:38][CH:37]=[CH:36][C:29]=2[N:30]2[C:35]=1[CH2:34][CH2:33][CH2:32][CH2:31]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[C:28]3[N:39]=[CH:38][CH:37]=[CH:36][C:29]=3[N:30]3[C:35]=2[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
Reactant: Brc1c2n(c3cccnc13)CCCC2
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: [K+]
Solvent: O
Solvent: COCCOC
Product: c1ccc2[nH]c(Oc3ccc(-c4c5n(c6cccnc46)CCCC5)cc3)nc2c1
Temperature: 150 °C
Yield: 13.2 %

Procedure:
To a suspension of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzo[d]imidazole (320 mg), 10-bromo-6,7,8,9-tetrahydropyrido[2,3-b]indolizine (217 mg) and K2CO3 (119 mg) in DME (4 mL) and water (1 mL) was added Pd(PPh3)4 (100 mg). The mixture was heated at 150° C. for 40 min under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (43.4 mg).