Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:6][CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Product: CCOC(=O)c1c[nH]c2cc(OC)c(OC)cc2c1=O
Yield: 40.5 %

Procedure:
3,4-Dimethoxyaniline (3.0 g) and diethyl ethoxymethylenemalonate (5.1 g) were subjected to condensation and ring closure in the same manner as in Experimental Example 1 to give 6,7-dimethoxy-3-ethoxycarbonyl-4(1H)-quinolone (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (53.8 mg, 0.525 mmol) (Aldrich), followed by the addition of 1-(4-isocyanato-phenyl)-ethanone (41.2 mg, 0.25 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (Yield 45 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[ClH:29].[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 86.4 %

Procedure:
A mixture of 13 g of 3-methyl 5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 7.85 g of 4,4-diphenylpiperidine hydrochloride and 12 g of potassium carbonate in 120 ml of toluene and 25 ml of water is refluxed for 14 h under a nitrogen atmosphere and with vigorous stirring. After cooling, the phases are separated; the organic phase is washed twice with water, dried over sodium sulphate and evaporated in vacuo. The oily residue is dissolved in 140 ml of dioxane, after which 2.3 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added and 20-25 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after trituration and is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80° C. 16 g of the title compound of m.p. 158°-160° C. and [α]22D =+14.4° (c=1, methanol) are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.Cl[Sn]Cl>C(O)C.CS(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CS(C)=O
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 6-nitro-7-bromo-1,4-dihydro-2,3-quinoxalinedione (87 mg, 0.30 mMol) in ethanol (3 mL) and DMSO (0.5 mL) was added SnCl2 ·2H2O (343 mg, 1.50 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution which was refluxed for another 1 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 50 mg (67%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 21 mg of pure as bright yellow needles, mp:>300° C. (dec. from 315° C.), changed color from 300° C. NMR (1H, DMSO-d6): d 5.257 (s, 2H); 6.558 (s, 1H); 7.087 (s, 1H); 11.599 (s, 1H); 11.792 (s, 1H). HRMS: calcd for C8H6N3O2Br (M+) m/z: 254.9642; found 254.9630. Potency relative to DCK: 7.1%.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].Br[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:25]([CH3:36])[CH:24]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:36][C:25]1[CH:24]=[C:23]([CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH:35]=[CH:34][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of N-propyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (69.8 mg, 0.25 mmol) in anhydrous MeCN (6 mL) under nitrogen at room temperature, was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (71.8 mg, 0.25 mmol) and N,N-diisopropyethylamine (43.5 μL, 0.25 mmol). The resultant mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (88 mg).
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[CH:23]=[C:22]([Cl:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[N:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:24][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:25]2[CH2:26][CH2:27][CH:28]([OH:31])[CH2:29][CH2:30]2)=[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])[CH:23]=1
Reactant: CC(N)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.096 g, 0.48 mmol), 1-[2-(1-aminoethyl)-4-chloro-1-naphthyl]piperidin-4-ol (0.074 g, 0.24 mmol), and N,N-diisopropylethylamine (0.084 mL, 0.48 mmol) in ethanol (0.8 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to dryness. 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 desired product as the free base. LCMS calculated for C22H24ClN6O (M+H)+: m/z=423.2; Found: 423.2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN1C(=O)CCC1.Cl.Cl.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:40]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:41]=2)=[CH:33][C:32]=1[C:53]([F:56])([F:55])[F:54].CCN(C(C)C)C(C)C.OP(O)(O)=O>>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([C:53]([F:55])([F:54])[F:56])[CH:33]=2)[N:38]=[C:39]1[CH:47]1[CH2:48][CH2:49][N:50]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)cc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Add a solution of 4-chloro-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (18.11 g; 1.05 equiv; 62.52 mmol) in NMP (156.50 mL; 1.62 mol) at RT to 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (31.30 g; 1.00 equiv; 59.54 mmol) and DIPEA (51.92 mL; 297.71 mmol) and stir overnight at 50° C. Quench the reaction with water (900 mL) and EA (200 mL) and adjust the pH of the mixture to 1-2 with H3PO4 [85% aqueous (aq.)]. Stir for 15 min and separate the phases. Extract the organic phase with a H3PO4 solution (15% aq. 3×100 mL). Wash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL). Adjust the pH of the aqueous phase to 9 with solid K2CO3 and extract with EA (3×15 mL). Wash the combined organic phases with brine, decolor with charcoal, and filter over Celite®. Combine the filtrates and evaporate. Crystallize the residue from EA/tBuOMe to obtain the title compound (17.00 g; 26.66 mmol; 44.77% yield) as pale rose solid. 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.91-7.83 (m, 2H), 7.43-7.40 (m, 2H), 7.17-7.11 (m, 2H), 6.86-6.81 (m, 2H), 4.87 (s, 2H), 4.56 (d, J=13.4 Hz, 2H), 4.13-4.07 (m, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.40-3.36 (m, 2H), 3.21-3.05 (m, 3H), 2.74 (t, J=6.6 Hz, 2H), 2.40-2.35 (m, 6H), 2.09-1.99 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-])=O)=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:21])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 93.8 %

Procedure:
A solution of methyl 5-tert-butoxycarbonylaminomethyl-2-nitrophenylacetate (6.8 g, 21 mmol) in methanol (250 mL) in the presence of 10% Pd/C was hydrogenated under atmospheric pressure of hydrogen at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated to give 5.8 g of the title compound.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH3:15]O.Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH3:15])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
Ferulic acid (4.85 g) and then methyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for 1 hour. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound. The product was crystallized from n-hexane to obtain a white crystal (5.09 g; 97.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
In a solution of 25.0 g of 3,5-dichlorophenyl boric acid in 200 ml of tetrahydrofuran and 100 ml of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 3 hours. After the completion of the reaction and cooling to room temperature, 500 ml of ice water was added, and extracted with ethyl acetate (500 ml×1). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane, and 25.7 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(CCCCCc3nnn[nH]3)oc2-c2ccc(Cl)cc2)cc1
Reaction time: 48 h
Yield: 45 %

Procedure:
The procedure is as in Example 2, heating for 48 hours 2.4 g of 6-[4,5-bis(4-chlorophenyl)-2-oxazolyl]hexanenitrile, 1.2 g of sodium azide and 1 g of ammonium chloride in 45 cm3 of dimethylformamide. Sodium azide and ammonium chloride are added (in the same quantities as before) and the mixture is brought again to 105° C. for 48 hours. The reaction product is extracted as in the abovementioned example and crystallised in 80 cm3 of diisopropyl ether. 1.2 g of 5-{5-[4,5-bis(4-chlorophenyl)-2-oxazolyl]pentyl}tetrazole, white crystals, melting point 100° C., are obtained.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:43])[CH:41]=O)=[CH:35][CH:34]=1.CC(O)=O>C1COCC1>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:43])[CH:41]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CC(C)C=O)cc1
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CC(C)C=Cc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
Potassium t-pentylat (1.7 M in toluene, 6.5 mL, 11.0 mmol, 1.1 equiv.) was added to a solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 15 min, 3-(4-methoxyphenyl)-2-methylpropanal (1.78 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 70° C. for 1.5 h. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was extracted with MTBE, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 19:1) to yield 2.20 g (74%) of the title compound as a yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]1)=[C:11]2[C:43]([O:45]C)=[O:44])(=[O:7])=[O:6])[CH3:4].[K]>CO.O>[CH2:3]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:12]([CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH2:33][CH2:32]1)=[C:11]2[C:43]([OH:45])=[O:44])(=[O:7])=[O:6])[CH3:4]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)OC)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Potassium hydroxide was added to a solution of methyl 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.0 g, 3.15 mmol) in methanol (60 mL) and water (20 mL) and reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and diluted with water. The methanol was removed under reduced pressure. The solid was collected by filtration, washed with cold water, and air dried to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.0 g, 96% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.13 (s, 1H), 7.92 (d, J=7.53 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.68 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 4.04 (s, 3H), 3.49-3.55 (m, 4H), 3.43-3.49 (m, 4H), 2.53-2.57 (m, 2H), 2.33-2.38 (m, 4H), 1.93-2.04 (m, 1H), 1.84 (t, J=11.04 Hz, 2H), 1.52 (d, J=11.29 Hz, 2H), 1.12 (t, J=7.28 Hz, 3H), 0.95-1.08 (m, 2H); MS (m/z) 622.2 (M+H+).
Reaction SMILES: O.NN.[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1)[CH3:5]>C(O)C.[Pd]>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH3:5]
Reactant: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCc1ccccc1Oc1ccc(N)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 208.7 %

Procedure:
In a 50 mL round-bottomed flask 2-[(2-ethylphenyl)oxy]-5-nitropyridine (Intermediate 45, 623 mg) was dissolved in ethanol (10 mL) to give a pale orange solution. Palladium on carbon (244 mg, 0.230 mmol) and hydrazine hydrate (0.442 mL, 4.59 mmol) were added. The reaction mixture was stirred at 90° C. After 3 hours the reaction was completed. The reaction mixture was filtered and the organic phase was evaporated under vacuum affording 1.1408 g of a dark orange solid that was charged on a 10 g SCX cartridge. It was then flushed with 200 mL of ethanol followed by 50 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as dark orange solid (456.1 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3ccccc3)cc2)OC1(C)C

Procedure:
Intermediate 23 was prepared in analogy to GP 4 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:5]([NH:7][CH:8]([NH:11][C:12]1[CH:22]=[CH:21][C:15]2[O:16][C:17]([F:20])([F:19])[O:18][C:14]=2[CH:13]=1)SC)=O.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][NH:33][NH2:34])[CH3:29].C(N(C(C)C)C(C)C)C>CC(O)(C)C>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][N:33]1[C:5]([C:4]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:2]([Cl:1])[CH:3]=2)=[N:7][C:8]([NH:11][C:12]2[CH:22]=[CH:21][C:15]3[O:16][C:17]([F:20])([F:19])[O:18][C:14]=3[CH:13]=2)=[N:34]1)[CH3:29]
Reactant: CSC(NC(=O)c1cc(C)nc(Cl)c1)Nc1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(Nc2ccc3c(c2)OC(F)(F)O3)nc1-c1cc(C)nc(Cl)c1
Temperature: 60 °C

Procedure:
Intermediate D2 (13.6 g; 0.0340 mol), 2-hydrazinylacetic acid ethyl ester, hydrochloride (1:1) (10.5 g; 0.0680 mol), N-ethyl-N-(1-methylethyl)-2-propanamine (13.2 g; 0.1020 mol) and t-BuOH (400 ml) were refluxed for 2 hours. The reaction mixture was then evaporated. Water was added and the product was extracted with CH2Cl2. The organic layer was dried on MgSO4, filtered and evaporated in vacuo. The residue was then heated to 60° C. in ethanol/HCl for 1 hour. The reaction mixture was partly evaporated and, the precipitate was filtered off and dried. Yield: 4.57 g of intermediate D3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:34])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(=O)O)s2)CC1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc3c(c2)ncn3-c2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a mixture of 0.048 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.3a), 0.046 g (0.12 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.008 g (0.15 mmole) of ammonium chloride and 1 mL of dimethylformamide was added 0.052 mL (0.3 mmole) of diisopropylethylamine. The mixture was stirred at ambient temperature for 1 hour, then filtered and purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.030 g of 4-(3-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.3) as a white powder. MH+/Z=467