Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (4.22 g, 25.4 mmol) in dry THF (100 mL) was added n-BuLi (17.9 mL, 28.7 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −78° C., a solution of N-methoxy-N-methylisonicotinamide (5.0 g, 31.8 mmol) in dry THF (15 mL) was added to reaction mixture and stirring was continued for an additional 2 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (80 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-3% EtOAc in Hexane to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (4.8 g, 57%) as an oil.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)CC>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:11]3([CH3:10])[O:12][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:13]3)[CH2:20][CH2:19]2)=[CH:26][CH:25]=1
Reactant: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 30.2 %

Procedure:
To a solution of 2-chloro-4-nitro-1H-imidazole (1.59 g, 10.8 mmol) and 1-(2-methyloxiran-2-ylmethyl)-4-(4-trifluoromethylphenyl)piperazine (3.23 g, 10.8 mmol) in 1-propanol (20 ml), sodium hydrogencarbonate (1.95 g, 23.8 mmol) was added followed by stirring under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-isopropyl ether to afford 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.34 g, yield 29%) as a a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1>CO.O1CCOCC1.[Ni]>[NH2:44][CH2:43][C:39]1[CH:38]=[C:37]([C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[O:29][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:12]3[S:16][N:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[C:5]([F:28])[CH:4]=2)[CH:42]=[CH:41][N:40]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3-c3ccnc(C#N)c3)cc2F)c(OC)c1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: NCc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2Cl)ccn1
Yield: 10 %

Procedure:
5-chloro-4-[4-chloro-2-(2-cyanopyridin-4-yl)phenoxy]-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 340, 0.04 g, 0.00006 mol) was partially dissolved in methanol (5.0 mL) and 1,4-dioxane (5.0 mL). The solution was passed through an H-Cube™ at 70° C. with Raney nickel catalyst (30 mm cartridge) 3 times eluting with methanol to get complete conversion. Concentration in vacuo afforded the title compound as a colourless solid, 0.004 g, 10% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([C:22]([O:24]C)=[O:23])([CH3:21])[CH3:20])[C:13](=[O:26])[C@@H:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([C:22]([OH:24])=[O:23])([CH3:20])[CH3:21])[C:13](=[O:26])[C@@H:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)CCN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1C(=O)N(CCC(C)(C)C(=O)O)CCN1C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 23B, (S)-4-(3-methoxycarbonyl-3-methyl-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester and 1 M aq. lithium hydroxide solution gave the titled compound in 70% yield as light yellow oil. MS: 363.19 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][O:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:16]1[CH:12]([CH2:11][NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[CH2:13][O:14][CH2:15]1
Reactant: ClCC1COCO1
Reactant: Cc1cccc(C)c1N
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: Cc1cccc(C)c1NCC1COCO1

Procedure:
2,6-Dimethylaniline (94.5 grams), 5-chloromethyl-1,3-dioxolane (31.8 grams), potassium carbonate (36.7 grams) and tetraethylammonium chloride (2 grams) 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 48 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-5-ylmethyl)-2,6-dimethylaniline having a boiling point of 132°C under aspirator pressure.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+].[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=2)[C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:10]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: Cc1sc(-c2ccccc2)cc1C(O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-2-methyl-5-phenylthiophene (909 mg) synthesized in Example 278 (6), methyl 5-amino-pyridine-2-carboxylate (438 mg), sodium iodide (863 mg) and N,N-dimethylformamide (10 mL) was added sodium carbonate (611 mg), and the mixture was stirred at 80° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-70% ethyl acetate/hexane) to give a pale-brown oil. To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred with heating under reflux overnight. The reaction mixture was concentrated under reduced pressure. 1N Hydrochloric acid (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (342 mg, 29%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[Cl:20]>C(O)C.Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[Cl:20]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(Cl)c1
Yield: 15 %

Procedure:
A solution of 1.39 g of 3-amino-5,5-dimethyl-2-cyclohexen-1-one and 793 mg of 4-fluoro-3-chlorobenzaldehyde in 10 ml of absolute ethanol and 1 ml of 1M aqueous hydrochloric acid was heated at reflux under a nitrogen atmosphere for 18 hours. The cooled mixture was filtered and the residue was washed with 25 ml of cold diethyl ether. Crystallization from absolute ethanol/water gave 302 mg of 9-(4-fluoro-3-chlorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione as a pale yellow crystalline solid of melting point 274-275° C. (decomposition).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[Cl:12][CH2:13][C:14]([O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19][CH:18]=1)=[O:15]>ClC(Cl)C>[C:5]([C:21]1[C:20]2[C:24](=[CH:25][C:17]([O:16][C:14](=[O:15])[CH2:13][Cl:12])=[CH:18][CH:19]=2)[N:23]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)n1ccc2ccc(OC(=O)CCl)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cn(C(=O)C(C)(C)C)c2cc(OC(=O)CCl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a suspension of 9.5 g (72 mmol) of aluminum chloride in dichloroethane (47.5 ml) was added dropwise 3.64 g (36 mmol) of acetic anhydride. After stirring for 15 min at room temperature, to the above mixture was added dropwise 3.3 g (11 mmol) of 6-chloroacetoxy-1-pivaloylindole (prepared in accordance with the literature (SYNTHESIS, p1018, 1994) in dichloroethane (33 ml). After stirring for 1 hour at room temperature, the mixture was poured into ice-water. The mixture was extracted with ethyl acetate. The extract was washed twice with water and aqueous sodium bicarbonate, and dried. The solution was concentrated and the obtained residue was chromatographed on silica gel (ethyl acetate as eluant) to give 1.23 g of 3-acetyl-6-chloroacetoxy-1-pivaloylindole as an oil. Yield: 36%.
Reaction SMILES: CS[C:3](=[N:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=1)[NH:4][C:5](=O)[CH2:6][C@@H:7]([O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8].[NH:40]([C:42]1[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=1)[NH2:41]>CN(C=O)C.[Hg](Cl)Cl>[CH3:24][C:23]([Si:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][C@@H:7]([CH3:8])[CH2:6][C:5]1[N:40]([C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)[N:41]=[C:3]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=2)[N:4]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(NN)ccn1
Reactant: CSC(=Nc1ccc(F)c(C(F)(F)F)c1)NC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc(Nc3ccc(F)c(C(F)(F)F)c3)nc2C[C@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccn1
Temperature: 80 °C

Procedure:
Mercury(II) chloride (1.8 g, 6.5 mmol) was added to a stirred solution of intermediate D9 (prepared according to Description 9) (3.8 g, 6.5 mmol) and 4-hydrazino-2-methylpyridine (0.8 g, 6.5 mmol) in DMF (65 mL) at room temperature. The reaction mixture was heated at 80° C. for 140 min. The cooled reaction mixture was poured onto ice and the precipitated product was collected by filtration to give a yellow semi-solid. Yield: 4.2 g of intermediate D14 (101.2%).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:5]([N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:34]2)=[N:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:11]=2)=[CH:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[C:5]([N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:34]2)=[N:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-(3-(prop-1-en-2-yl)-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate (60.50 mg, 0.09426 mmol) and palladium hydroxide on carbon 20% (0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol (30 mL) in a round bottom flask was vacuumed and connected to a Hydrogen balloon. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through Celite. The filtrate was concentrated to afford (S)-tert-butyl 1-(3-isopropyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate, which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene chloride (3 mL), and treated with Trifluoromethanesulfonic acid (83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 328 as an off-white solid (8.2 mg, 21%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=2.1 Hz, 1H), 9.22 (s, 1H), 9.06 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 2.90 (d, J=9.1 Hz, 2H), 2.00 (d, J=12.6 Hz, 1H), 1.90 (d, J=13.4 Hz, 1H), 1.76 (dd, J=24.1, 11.0 Hz, 1H), 1.46-1.34 (m, 1H), 1.25 (t, J=6.9 Hz, 6H); ESI MS m/z=414.2 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C1C=CN=C(C2C=CC=CN=2)C=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: Oc1cc(Br)ccn1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccn2)nc1
Product: O=c1cc(Br)ccn1C1CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromopyridin-2-ol (100 mg, 0.58 mmol), cyclopropylboronic acid (100 mg, 1.3 mmol), Cu(OAc)2 (245 mg, 1.2 mmol), and bipyridine (100 mg, 0.64 mmol) in Cl(CH2)2C1 (5.0 mL) was stirred for 24 h at 70° C. The crude mixture was filtered. The filtrate was collected and concentrated to afford the crude product, which was purified by silica gel column chromatography on silica gel with PE/EA (5:1) to afford tittle compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 1 H), 6.79 (d, 1 H), 6.31 (dd, 1 H), 3.34-3.23 (m, 1 H), 1.14 (d, 2 H), 0.86 (d, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([C:31]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(N)n1
Reactant: O=C(Cl)C1CCC1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (28 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:20][N:19]([CH2:18][C:14]1[N:13]([C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([C:9]([F:10])([F:12])[F:11])[CH:5]=2)[NH2:1])[CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: CN(C)Cc1ncc[nH]1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
3-Amino-5-bromobenzotrifluoride (6 g, 25 mmol) and 1-(1H-imidazol-2-yl)-N,N-dimethylmethanamine (3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 mL). To this was added Cul (0.95 g, 7.5 mmol), 8-hydroxy quinoline (0.72 g, 7.5 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N2 for 15 minutes. The flask was then equipped with a condenser and heated at 120° C. for 18 h. The resultant heterogeneous mixture was cooled to rt, poured into 14% aq. NH4OH (100 mL) and extracted with EtOAc (3×300 ml). The combined extracts were dried over NaSO4 and concentrated in vacuo. The residue was chromatograhed over silica gel eluting with MeOH/DCM (5:95) to furnish 3.5 g of the desired product as a tan colored material: 285 m/z (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8](OC)[CH:7]=[N:6]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:10](=[O:11])[CH:9]=1
Reactant: COCCn1ncc(OC)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COCCn1ncc(Cl)cc1=O

Procedure:
The title compound, light yellow oil, was prepared in accordance with the general method of example 23c by treatment of 2-(2-methoxy-ethyl)-5-methoxy-2H-pyridazin-3-one with phosphorus oxychloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[NH:24][N:23]=[N:22][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1ccc(COc2cccc(Cc3nnn[nH]3)c2)cc1
Temperature: 110 °C

Procedure:
To a stirring solution of 3-benzyloxyphenylacetonitrile (2.0 g, 8.95 mmol) in toluene (17 ml) was added trimethylsilylazide (2.37 g, 17.9 mmol) and di-n-butyltin oxide (0.22 g, 0.9 mmol). The mixture was heated at 110° C. for 48 h, and was concentrated. The reaction mixture was dissolved in ethyl acetate (100 ml) and washed two times with 10% aqueous sodium bicarbonate. The basic extracts were acidified to pH<2 with conc. HCl, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product (2.0 g, 89%) was used in the next step without further purification. MS (ESI) 267.0 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(Nc2ccc(Cl)c(Cl)c2)c2nc[nH]c2n1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(Cl)c(Cl)c3)c3nc[nH]c3n2)CC1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2140 mg of the product obtained in stage 1 above are added. 50 mg of the expected product are thus obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH:29][CH3:30]>>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:5]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CNCCOC
Product: COCCN(C)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OC)n1
Yield: 51 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and N-(2-methoxyethyl)methylamine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 51% yield.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.92 min; [M+H]+=422.07.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:3]=[C:2]2[C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1CNc1cc(Br)c2cc(Cl)ccc2n1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(Cl)ccc2n1

Procedure:
(4-Bromo-6-chloro-quinolin-2-yl)-(2-methoxy-benzyl)-amine (530 mg, 1.4 mmol) and pyridine-3-boronic acid (224 mg, 1.8 mmol) were dissolved in 16 mL dimethoxyethane and 8 mL 2N sodium carbonate solution. The reaction mixture was evacuated and backfilled with argon for three times. Triphenylphosphine (37 mg, 0.141 mmol) and palladium acetate (16 mg, 0.071 mmol) were added and the mixture was refluxed overnight. The mixture was extracted three times with ethyl acetate (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->30:70 gradient). (6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a white foam (500 mg, 94%), MS: m/e=376.4 (M+H+).