Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][NH:5][C:4]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1OCCO1
Reactant: CCc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCC1OCCO1

Procedure:
2-Ethyl-6-methylaniline (70 grams), 2-chloromethyl-1,3-dioxolane (30 grams), potassium carbonate (38 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of about 24 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH:15]([C:16]([O:18][CH3:19])=[O:17])[C:20]([O:22][CH3:23])=[O:21])[CH2:13][CH2:14]1
Reactant: COC(=O)C(C(=O)OC)[C@H]1CC[C@@H](NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)[C@H]1CC[C@@H](N)CC1

Procedure:
23.0 g of dimethyl (cis-4-benzylaminocyclohexyl)malonate were dissolved in 200 ml of methanol and hydrogenated at 30 bar and 50° C. in the presence of 2 g of palladium catalyst (5% on carbon). Removal of the catalyst by filtration and subsequent concentration gave 16.0 g of the title product as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH3:18])[C:10]([NH:15][CH3:16])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH:22]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH3:18])[C:10]2[N:15]([CH3:16])[CH:22]3[O:24][CH:19]([C:11]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:21]3)=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])NC
Reactant: O=CCCC=O
Agent: Cl
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C1=C([N+](=O)[O-])C2CCC(O2)N1C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a 50 ml round bottom flask was added 1.35 g (0.005 mol) N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N′-methyl-2-nitroethene-1,1-diamine, 30 ml dry acetonitrile, 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 40% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1.CO>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5B (0.500 g, 0.992 mmol) and (trans)-cyclohexane-1,4-diamine (1.360 g, 11.91 mmol) in NMP (2.5 mL) was subjected to 110° C. in a 300 W CEM Discover microwave for 20 min. The mixture was diluted with MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=42 min. 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (0.500 g, 54.6% yield) was obtained as a light yellow solid. LC/MS, m/z 582.1 (M+1). HPLC Rt=3.211 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, d, J=1.76 Hz), 8.69 (1H, d, J=2.77 Hz), 8.46-8.53 (1H, m), 8.41-8.47 (1H, m), 8.28 (1H, dd, J=4.78, 1.26 Hz), 8.01 (1H, s), 7.89 (2H, d, J=4.28 Hz), 7.57-7.72 (1H, m), 7.26 (2H, d, J=8.81 Hz), 7.18 (1H, d, J=7.81 Hz), 7.11 (1H, d, J=8.31 Hz), 7.03 (1H, dd, J=6.55, 5.04 Hz), 6.83 (2H, d, J=8.81 Hz), 6.52 (1H, s), 5.43 (2H, s), 3.72-3.84 (1H, m), 3.64-3.72 (3H, s), 3.06 (1H, d, J=4.78 Hz), 2.03-2.15 (2H, m), 1.95 (2H, d, J=10.07 Hz), 1.34-1.49 (2H, m), 1.26 (2H, d, J=12.34 Hz).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:32]([C:34]1[S:35][CH:36]=[CH:37][C:38]=1[C:39](O)=[O:40])=O>>[OH:26][CH2:25][C:11]1[N:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:1]3[C:39](=[O:40])[C:38]4[CH:37]=[CH:36][S:35][C:34]=4[C:32]([C:31]4[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:29]([O:28][CH3:27])[CH:30]=4)=[N:2]3)[CH:8]=2)[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=2
Reactant: COc1cc(C(=O)c2sccc2C(=O)O)cc(OC)c1OC
Reactant: CCOc1cc2cc(CO)nc(-c3ccnc(NN)c3)c2cc1OCC
Product: CCOc1cc2cc(CO)nc(-c3ccnc(-n4nc(-c5cc(OC)c(OC)c(OC)c5)c5sccc5c4=O)c3)c2cc1OCC

Procedure:
2-Hydrazino-4-(3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl)pyridine and 2-(3,4,5-trimethoxybenzoyl)-3-thiophenecarboxylic acid are treated in the same manner as in Example 7-(4) to give 4-(3-hydroxymethyl-6,7-diethoxyisoquinolin-1-yl)-2-[7-(3,4,5-trimethoxyphenyl)thieno[2,3-d]pyridazin-4(5H)-on-5-yl]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(-c2ncc(Br)cc2N)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(3-methoxyphenyl)pyridin-3-amine (0.156 g, 0.56 mmol) in dry DMF (10.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.0454 g, 1.14 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.25 g, 0.86 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-2-(3-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=533.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.O[N:37]1[C:41]2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[CH3:41][NH:37][C:30]([C:29]1[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11](N)[CH:12]=1.N([O-])=[O:16].[Na+].NC(N)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([OH:16])[CH:12]=1
Reactant: Cc1ccc(F)cc1N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2-methylphenylamine (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0° C. for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130° C. over 10 minutes. After an additional 5 minutes at 130° C., the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HCl and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(O)C>[ClH:31].[ClH:31].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(NCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.37 g (7.86 mM) of N-[2-(1-tert-butoxycarbonyl-4-piperidyl)ethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (100 ml) was added 12N-hydrochloric acid (3.2 ml, 39.3 mM) and the mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and rinsed with small amounts of ethanol and ether to provide the title compound.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
p-toluenesulfonic anhydride (520 mg, 1.59 mmol) and N,N-diisopropylethylamine (300 μl, 1.72 mmol) are added to an ice-cold, stirring solution of p-nitrobenzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (484 mg, 1.59 mmol) in anhydrous methylene chloride (17 ml). The resulting solution is stirred in the cold for 2 hours, then diluted with more methylene chloride, washed with water, 1μ ph 3.4 phosphate buffer and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and evaporated under vacuum. Addition of cold ethyl acetate and a few seeds crystals to the oily residue induces crystallization. The product is collected, washed with cold ethyl acetate, and dried under vacuum to afford p-nitrobenzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (446 mg, 61%) as off-white crystals: mp 99°-102° (dec.); IR (neat) 1790, 1725, 1521, 1345, and 1172 cm-1 ; UV (CH2Cl2) 272 nm; NMR (CDCl3) δ 2.40 (s, 3, ArCH3), 3.06 (dd, 1, J=3.0 and 17.2, H6β), 3.16 (dd, 1, J=9.0 and 9.0, H4a), 3.31 (dd, 1, J=9.0 and 10.0, H4b), 3.59 (dd, 1, J=5.8 and 17.2, H6α), 4.24 (m, 1, H5), 5.20 and 5.32 (ABq, 2, J=14.0, CH2Ar), 7.32 and 7.77 (two d's, 4, J=8.0, p-MeC6H4), 7.51 and 8.19 (two d's, 4, J=8.0, p-NO2C6H4).
Reaction SMILES: [OH-].[K+].CO.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:11]=[CH:10]2>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: CCOC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 25 °C

Procedure:
To the benzene solution of bis(6-methoxy-2-naphthyl)zinc formed in Example 61 above is added 9.96 grams of ethyl 2-bromopropionate in 5 mL of anhydrous benzene. The temperature of the reaction mixture is maintained at from 50° to 55° C. for 15 hours, under nitrogen, and then the reaction mixture is mixed with 175 mL of 1.5N hydrochloric acid solution, followed by 65 mL of methylene chloride. The mixture is filtered, and the organic phase is separated. The aqueous acid layer is extracted with two further 30 mL quantities of methylene chloride, and the methylene chloride extracts are combined, washed with 50 mL of water, and stripped of solvents under vacuum to yield ethyl 2-(6-methoxy-2-naphthyl)propionate. A solution of 6.0 grams of potassium hydroxide, 6 mL of water and 60 mL of methanol is added to the ethyl 2-(6-methoxy-2-naphthyl)propionate, and the mixture is heated at reflux for 45 minutes, cooled to ambient temperature, acidified and mixed with 60 mL of water. Methanol is removed by evaporation in vacuo, and the resultant solution is extracted with two 60 mL portions of methylene chloride. The combined methylene chloride extracts are evaporated to dryness to yield 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]([N:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:28]([C@@H:30]1[C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][N:32]([C@H:41]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:42]([O:44]CC2C=CC(OC)=CC=2)=[O:43])[CH2:31]1)=O>>[CH2:8]([NH:15][C:16]([N:18]([CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C@@H:30]2[C@@H:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:33][N:32]([C@H:41]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[C:42]([OH:44])=[O:43])[CH2:31]2)[CH2:26][CH2:27]1)[CH2:19][CH2:20][CH3:21])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: CCCN(C(=O)NCc1ccccc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccccc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 39.8 %

Procedure:
The title compound was prepared from 4-(N-(N-benzylcarbamoyl)-N(prop-1-yl)amino)-piperidine trifluoroacetate (19 mg, 0.048 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (14 mg, 0.028 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 6.4 mg (40%) of the title compound. ESI-MS: 575.4 (M+H); HPLC A: 2.32 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>Br.C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1C(F)(F)F

Procedure:
A solution of 3.0 g (11.8 mmol) 4-bromo-1-methoxy-2-trifluoromethyl-benzene in 20 mL 1 M HBr in glacial acetic acid is stirred for 60 h at 90° C. The reaction solution is diluted with 300 mL water, adjusted to pH 7 with K2CO3. The aqueous phase is extracted with EtOAc, the combined organic extracts are with washed 40 mL quarter-saturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and the product is further reacted without any more purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6])(=[O:37])[CH3:36]
Reactant: Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(F)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(F)cc2)c1
Yield: 98.3 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-fluorophenyl)benzamide (223.2 mg, 0.48 mmol) and acetic anhydride (0.055 ml, 0.58 mmol), the procedure of inventive Example 94 was repeated to obtain 238.6 mg (98.3%) of the title compound in a light yellow amorphous form.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[C:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([CH:22]1[CH2:27][CH2:26][N:25]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:24][CH2:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: CC(C)(C)C1CCNCC1
Product: CC(C)(C)C1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 536 mg (3.80 mmol) of 4-tert-butylpiperidine to give 57 mg (42% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([OH:28])[CH3:27])=[CH:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:41](Br)[CH:42]=[CH:43][CH3:44].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([O:28][CH2:41]/[CH:42]=[CH:43]/[CH3:44])[CH3:27])=[CH:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=CCBr
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C/C=C/COC(C)C1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 70 mg of 4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 2 mL of DMSO was treated with 0.22 mL of 1.0 M sodium bis(trimethylsilyl)amide and 29 mg of crotyl bromide at room temperature. The reaction mixture was allowed to stir at room temperature overnight. The reaction was worked up by adding water and extracted with EtOAc three times. The organic layers were combined, washed sequentially with saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield 58 mg of 4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:11][C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([OH:9])=[O:8])=[CH:6][N:1]=1)=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C

Procedure:
To a suspension of pyridine-2,5-dicarboxylic acid (4.2 g, 25.1 mmol) (Aldrich) in methanol (50 mL) was added concentrated sulfuric acid (1.5 g, 15.3 mmol) (Aldrich). The mixture was heated at refluxing for 2 hours. The crude was cooled down to room temperature and poured into water (250 mL). The precipitate formed was collected and washed with methanol to give pyridine-2,5-dicarboxylic acid-2-methyl ester as a grey solid. (Yield 1.5 g, 33%).