Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])=[CH:9][N:10]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][C:6]1[S:7][C:8]([C:11]2[CH2:18][O:17][CH:16]3[N:13]([C:14](=[O:39])[CH:15]3[NH:19][C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[C:40]([O:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)C3OC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of acetyl chloride (0.11g) in dry tetrahydrofuran (2 cc) is added, in 3 minutes, to a solution, cooled to 0° C., of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.80 g) in dry tetrahydrofuran (10 cc), and a solution of triethylamine (0.18 cc) in dry tetrahydrofuran (2 cc) is then added. The mixture is stirred for 30 minutes at 0° C. and is then filtered over a diatomaceous earth powder. The filtrate is diluted with ethyl acetate (50 cc) and washed with distilled water (50 cc), a half-saturated sodium bicarbonate solution (50 cc) and a saturated sodium chloride solution (50 cc). The organic phase is dried over anhydrous sodium sulphate; it is filtered, the insoluble matter is washed with ethyl acetate (10 cc) and the organic solution is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue (0.89 g) is chromatographed on a column (height: 24 cm; diameter: 2.2 cm) of silica (0.04-0.06 mm), elution being carried out with a 40:60 (by volume) mixture of cyclohexane and ethyl acetate under 0.4 kPa, and 60 cc fractions being collected. Fractions 5 to 11 are combined and the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-tritylamino-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.55 g) is obtained in the form of a pale chestnut-coloured froth.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[S:7][CH:8]=1)([CH3:3])[CH3:2].Cl[C:23]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:30]2[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:4]1[N:5]=[C:6]([C:23]2[CH:32]=[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:30]3[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=3)[N:24]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nc(C(C)C)cs3)nc3c(C)cc(OC)cc23)cc1
Yield: 63 %

Procedure:
Compound 219 (100 mg, 0.29 mmol), compound 221f (242 mg, 0.35 mmol), and potassium carbonate (48 mg, 0.35 mmol) in degassed anhydrous DMF were stirred under microwave radiations at 80° C. for 1 hr. Solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel (Petroleum ether/DCM) to yield compound 222f as yellow powder in 63% yield. 1H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.42 (s, 3H), 2.80 (s, 3H), 3.17-3.24 (m, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 5.31 (s, 2H), 6.99 (d, J=9.10 Hz, 2H), 7.00 (s, 1H), 7.21 (m, 1H), 7.31 (d, J=2.93 Hz, 1H), 7.49 (d, J=9.10 Hz, 2H), 7.79 (s, 1H).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17](Cl)=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]>C1COCC1.[Cu]I>[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]
Reactant: Cc1nc(Cl)cc(Cl)c1C(=O)OC(C)C
Reactant: CC(C)O
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous isopropanol (1.5 mL, 20 mmol) is added to a suspension of NaH (1.5 g of 60% dispersion in mineral oil, 37 mmol) in THF (90 mL) at 0° C. and the mixture is stirred for 30 minutes at ambient temperature. To this is added a solution of 4,6-dichloro-2-methyl-nicotinic acid isopropyl ester (4.6 g, 19 mmol) in THF (10 mL) and CuI (178 mg, 0.94 mmol) The mixture is refluxed for 1 hour, cooled to room temperature, and poured into water-ice mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 61) to yield 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester as a pale yellow oil. 1H NMR (CDCl3) 6.65 (s, 1H), 5.24 (m, 1H), 4.60 (m, 1H), 2.41 (s, 3H), 1.28 (d, 12H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1C=O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:3]=[CH:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 31 %

Procedure:
33 g (250 millimoles) of monoethyl malonate and 27 g (150 millimoles) of 2-chloro-5-nitrobenzaldehyde in 100 ml of pyridine were reacted similarly to Example 1, and the mixture was worked up in a conventional manner. Yield: 31%, mp. 138°-140° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-yl-amine (prepared in Example 72, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 86%) as a colorless oil: [α]30589=−18.8° (c=0.16, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 2.05-2.19 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.86-3.94 (m, 1H, ArCH), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.75 (m, 4H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][CH2:27][CH2:28]O)[CH2:9][C@@H:10]([NH:12][S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[N:21][CH:20]=[CH:19]2)(=[O:15])=[O:14])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:32]([C@@H]1CNCCCN1S(C1C=C2C(=CC=1)C=NC=C2)(=O)=O)C.Cl.Cl.CN[C@H]1CCN(S(C2C=C3C(=CC=2)C=NC=C3)(=O)=O)C1>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:27][CH2:28][N:12]([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[N:21][CH:20]=[CH:19]3)(=[O:15])=[O:14])[C@H:10]([CH2:11][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[C@@H]1CNCCCN1S(=O)(=O)c1ccc2cnccc2c1
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Agent: CN[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Agent: Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1

Procedure:
The compound of interest was synthesized according to the production method of Step 1 of Example 12 using Reference Compound 2 and using Reference Compound 19 instead of Reference Compound 10.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCCl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-piperidylcarboxylate (100 g, 0.64 mole) in acetone (600 ml) was treated with 1-bromo-2-chloroethane (54 ml, 0.64 mole) and anhydrous potassium carbonate (138 g, 1.00 mole) and the mixture stirred at room temperature for 24h. The mixture was concentrated in vacuo and the residue treated with water (400 ml) and extracted with ether (2×200 ml). The combined ether extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by chromatography on silica gel eluting with 50% ether/60-80 petrol to give the title compound (D18) as a pale yellow oil (50.0 g, 36%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(OCC)=O)C.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:12](#[N:13])[CH:11]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1ccccc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Four grams of 60% sodium hydride was suspended in 100 ml tetrahydrofuran, and 17.1 g of diethylphosphonoacetonitrile was added with ice cooling. To the resulting solution, was added dropwise a solution of 10.6 g benzaldehyde in 80 ml tetrahydrofuran, and the mixture was stirred for one hour. After admixing 50 ml water, the organic layer was collected, dried over anhydrous sodium sulfate and concentrated. Distillation of the concentrate under reduced pressure (102°-106° C./6 mmHg) gave 8.9 g (yield: 69.0%) of cinnamonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].COCCl.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4-hydroxyphenyl)ethanol (1.4 g) in tetrahydrofuran (30 ml) was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the stirred reaction mixture was added chloromethyl methyl ether (770 μl) under ice-cooling, and the resulting mixture was stirred for 16 hours at room temperature. Additionally, to the stirred reaction mixture was added 60% sodium hydride in mineral oil (405 mg) under ice-cooling. After the mixture was stirred for 1 hour at room temperature, benzyl bromide (1.2 ml) was added under ice-cooling and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 ml), trifluoroacetic acid (20 ml) was added to the solution under ice-cooling with stirring, and the mixture was stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution (20 ml) and water (20 ml) were added to the residue, and the resulting mixture was vigorously shaken. The aqueous layer was separated, washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave 4-(2-benzyloxyethyl)phenol (440 mg).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al](C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:22]([C:30](OCC)=[O:31])[N:21]=[C:20]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>ClCCl.CCCCCCC>[CH:1]1([NH:7][C:30]([C:22]2[N:21]=[C:20]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])[N:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C(NC1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Part C: Cyclohexylamine (0.91 ml, 8 mmol) is dissolved in dichloromethane (20 ml) and (CH3)3Al (4 ml of a 2 M solution in heptane, 8 mmol) is added. The resulting mixture is stirred for 10 minutes at room temperature and ethyl 1-(4-chlorophenyl)2-(2,4-dichlorophenyl)-5-(pyrolidin-1-ylmethyl)-1H-imidazole4-carboxylate (1.8 gram, 3.8 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours, poured into an aqueous NaHCO3 solution, stirred for 30 minutes and filtered over hyflo. The filtrated is twice extracted with dichloromethane. The organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (dichloromethane/methanol=98/2 (v/v)) gives N-cyclohexyl-1-(4-chlorophenyl )-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide, compound 1 (1.06 gram, 53% yield). Melting point: 155-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](Br)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1)#[CH:34]>C1(C)C=CC=CC=1.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.[Cu]I>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(C#Cc3ccc(C(F)(F)F)cc3)c2)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
300 mg (0.74 mmol) of the compound of step 1 and 90.1 mg (0.89 mmol) of triethylamine were dissolved in 10 ml of dry toluene. 171.5 mg (148 μmol) of tetrakis(triphenylphosphine)palladium(0) and 14.1 mg (74 μmol) of copper(I) iodide were added, and the mixture was stirred for 30 min. Subsequently 126.2 mg (0.74 mmol) of 1-ethynyl-4-trifluoromethyl-benzene were added and the mixture was heated to 100° C. for 10 h. The mixture was filtered, the solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 40 mg of the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[O:15][CH:16]=2)=[CH:8][CH:7]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[C:14]2[O:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:29]=[CH:30][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:7][CH:8]=3)[N:13]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 57.1 %

Procedure:
A suspension of 4-[[4-(4-iodobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (6.00 g), ethyl 3-(1H-imidazol-2-yl)propionate (3.83 g) and potassium carbonate (1.58 g) in DMF (100 ml) was stirred at 70° C. for 23 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) and washed with diethyl ether-hexane to give the titled compound (3.69 g) as a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[C:10]=2[F:12])[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:15]=[N:14][C:13]([C:9]2[C:10]([F:12])=[C:11]3[C:6]([CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=[C:2]3[F:1])=[CH:7][CH:8]=2)=[N:18][CH:17]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2ccc(-c3ncc(O)cn3)c(F)c2c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc3cc(OCCCCCCCC)nc(F)c3c2F)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1,8-difluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxyisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1 -octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1,8-difluoro-3-octyloxyisoquinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[C:4](=[CH2:11])/[C:3]/1=[C:12](/[O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])\[CH:13]=[CH2:14].[CH3:21]C1C(C)(C)C(C)=C(C)C(C)(C)C=1C(OC)=O>>[CH3:1][C:2]1([CH3:20])[C:7]([CH3:21])=[C:6]([CH3:8])[C:5]([CH3:9])([CH3:10])[C:4](=[CH2:11])/[C:3]/1=[C:12](/[O:15][Si:16]([CH3:18])([CH3:19])[CH3:17])\[CH:13]=[CH2:14]
Reactant: COC(=O)C1=C(C)C(C)(C)C(C)=C(C)C1(C)C
Reactant: C=C/C(O[Si](C)(C)C)=C1\C(=C)C(C)(C)C(C)=CC1(C)C
Product: C=C/C(O[Si](C)(C)C)=C1\C(=C)C(C)(C)C(C)=C(C)C1(C)C
Yield: 75 %

Procedure:
As described above for (5a) provided it used (4b) as starting material. Yield: 75%.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2].F[C:29](C1C=CC=CC=1)(F)F.F[B-](F)(F)F.C[O+](C)C>C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:29])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: FC(F)(F)c1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCSc1nc2c(OC)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (40 mg) and (trifluoromethyl)benzene (10 ml) was added trimethyloxonium tetrafluoroborate (22 mg) at room temperature, and the reaction mixture was heated under reflux for 3 hr, allowed to be cooled to room temperature, and diluted with ethyl acetate. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (16 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][NH:12]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][NH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Temperature: -15 °C

Procedure:
Protected amide 1-6 (576 mg, 1.26 mmol) was dissolved in 6.3 mL CH2Cl2, cooled to -15° C., and TFA (6.3 mL) was added. After 25 min the reaction was concentrated, providing amine 1-7.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)N(C)CC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:12]1([NH:18][C:2]2[C:3]3[CH:11]=[CH:10][NH:9][C:4]=3[N:5]=[CH:6][C:7]=2[F:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: Fc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 200 °C
Yield: 12.2 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and cyclohexylamine (87 mg) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 4 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave N-cyclohexyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.