Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:14]=1[C:28]([F:31])([F:30])[F:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:32][C:33]1[C:34]([C:42]#[N:43])=[N:35][C:36](Cl)=[CH:37][C:38]=1[NH:39][CH3:40].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.O>[NH2:32][C:33]1[C:38]([NH:39][CH3:40])=[CH:37][C:36]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])=[C:14]([C:28]([F:29])([F:30])[F:31])[CH:15]=2)=[N:35][C:34]=1[C:42]#[N:43]
Reactant: CN(CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(-c2ccc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N

Procedure:
tert-Butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)carbamate (22.46 mmol, 10 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (22.46 mmol, 4.10 g), potassium phosphate (67.4 mmol, 14.30 g), tricyclohexylphosphine (2.69 mmol, 0.756 g), and tris(dibenzylacetone)-dipalladium (0) (1.123 mmol, 1.028 g) were dissolved in Dioxane (20 ml) and Water (10.00 ml) and stirred under nitrogen at 100° C. for 2 hrs. The mixture was diluted with ethyl acetate and filtered through celite. Organic layer was washed with water and separated from the aqueous layer, the organic layer was concentrated in vacuo. This was purified by silica chromatography, eluting with heptane—50/50 heptane/EtOAc to afford tert-butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl(methyl)carbamate. (2.11 g)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCCO
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CCO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)ethanol (40 mg, 0.53 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving the title compound (106 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]O.[C:22]1([OH:29])[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1.B(F)(F)F.CCOCC.O>O1CCOCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][C:27]1[CH:26]=[CH:25][C:24]([OH:28])=[CH:23][C:22]=1[OH:29]
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Oc1cccc(O)c1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
3,7,11,15-Tetramethyl-2-hexadecen-1-ol(14.8 g; 50 mmole) in 15 ml of dioxane was dropwise added to 11.0 g (100 mmole) of 1,3-benzenediol and 4.3 g (30 mmole) of boron trifluoride ethyl etherate in 30 ml of diozane at room temperature over one hour. After stirring the reaction solution at that temperature overnight, the solution was poured into 75 ml of water and was extracted with isopropyl ether (100 ml). The extract was washed with 200 ml of water (3 times) and 200 ml of saturated aqueous solution of sodium chloride (3 times) followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resulting residue to silica gel column chromatography to thereby obtain 2.80 g of the title compound from the fractions eluted with hexane-ethyl acetate (3:1). Yield=14%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:15]#[N:16])=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]2[C:13]=1[C:14]([C:5]#[N:6])=[CH:15][NH:16]2
Reactant: Cc1cc(O)c2cc[nH]c2c1
Reactant: Oc1cccc2[nH]ccc12
Product: Cc1cc(O)c2c(C#N)c[nH]c2c1
Product: N#Cc1c[nH]c2cccc(O)c12

Procedure:
Compounds of general formula (I) can be further reacted by known methods, for example by saponification and decarboxylation to give 4-hydroxyindole or 4-hydroxy-6-methylindole, or by aminolysis and dehydration to give 4-hydroxy-3-cyanoindole or 4-hydroxy-3-cyano-6-methylindole, which, by reaction with epichlorohydrin and alkylamino derivatives, give aminopropanols with useful pharmacological properties (see Federal Republic of Germany Patent Specification Nos. 25 08 251; 27 37 630; 29 05 877 and 30 30 047). However, compounds of general formula (I) can also be reacted to give aminopropanol derivatives directly, whereafter the compounds obtained are subsequently changed. Thus, for example, from 4-hydroxy-3-cyanoindole (see Federal Republic of Germany Patent Specification No. 30 29 980) there is obtained 4-(2,3-epoxypropoxy)-3-cyanoindole which is reacted with 2-(2-allyloxyphenoxy)-ethylamine to give the pharmacologically effective 4-{2-hydroxy-3-[2-(2-allyloxyphenoxy)-ethylamino]-propoxy}-3-cyanoindole (see Example 3h) of Federal Republic of Germany Patent Specification No. 30 30 047).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([NH2:31])[N:28]=[C:29](Cl)[C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:31][C:27]1[N:28]=[C:29]([O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[C:24]2[CH:23]=[CH:22][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:25]=2[N:26]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in 1-methyl-2-pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in 1-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH2:20])[CH3:19].CCO>C(CC(C)(C)C)(C)C>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH2:18][CH3:19])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CCN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 130 °C

Procedure:
A mixture of 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), ethanamine (0.5 ml, 2 M in MeOH) and EtOH (3 ml) was heated under microwave radiation at 130° C. for 30 min. MS m/z (rel. intensity, 70 eV) 289 (M+, 0.3), 176 (7), 141 (8), 95 (9), 75 (10), 58 (bp).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:18][CH2:17]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCN)cc2)CC1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 41.2 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-octyl-1-piperidinecarboxamide formate (0.40 g, 0.916 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.37 g, 0.916 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.30 g, 0.377 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[CH3:15][C:16]1([CH3:35])[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:19]2[C:28]([CH3:34])=[CH:29][C:30]([CH3:33])=[C:31]([CH3:32])[C:18]=2[O:17]1.C(#[N:38])C>Cl.O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]=[N:38][C:29]2[C:30]([CH3:33])=[C:31]([CH3:32])[C:18]3[O:17][C:16]([CH3:35])([CH3:15])[CH:20]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:19]=3[C:28]=2[CH3:34])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(C2c3c(C)cc(C)c(C)c3OC2(C)C)cc1
Reactant: CC#N
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C2c3c(C)c(N=Nc4ccc([N+](=O)[O-])cc4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4-Nitroaniline (10.4 g) was dissolved in 2N hydrochloric acid (150 mL) by heating, and then cooled to 0 to 5° C. To the solution was added a solution of sodium nitrite (5.2 g) in water (15 mL), and the mixture was stirred for 15 minutes. To the mixture were added 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (14.0 g) and acetonitrile (150 mL). The reaction mixture was stirred at 65 to 70° C. for one hour under a nitrogen atmosphere, and then allowed to cool to room temperature. Precipitated crystals were collected by filtration, and washed with 1N hydrochloric acid and water. The crystals were dried under reduced pressure to obtain the title compound as a brown solid (21.0 g, yield 100%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]([CH3:23])([CH3:22])[CH2:6]1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:33].[Na+].OO>O1CCCC1.O.CCOCC>[CH2:14]([O:13][N:8]1[C:7]([CH3:22])([CH3:23])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][OH:33])[CH2:10][C:9]1([CH3:11])[CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCON1C(C)(C)CC(OCCCO)CC1(C)C
Temperature: 20 °C
Yield: 88.8 %

Procedure:
A solution of 14.9 grams (45.9 mmol) of 4-allyloxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 10A) in 20 ml of anhydrous tetrahydrofuran is added over a 10-minute period to a solution of 5.6 grams (45.9 mmol ) of 9-borabicyclo [3.3.1]nonane in 20 ml of tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is cooled to 20° C., and a solution of 1.84 gram ( 45.9 mmol ) of sodium hydroxide in water is added over a 10-minute period. A solution of 15.3 ml of 30% aqueous hydrogen peroxide is then added over 30 minutes while the reaction mixture is cooled in an ice-water bath. The reaction mixture is diluted with ether (50 ml) and the organic layer is separated and dried over potassium carbonate. Solvent is evaporated and the residue is purified by flash chromatography (silica gel; 2:1 heptane:ethyl acetate) to afford 14.0 grams (89% yield) of the title compound is a colorless syrup.
Reaction SMILES: CNC1CCCCC1NC.O1CCOCC1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2.[Na+].[I-:39]>[Cu]I.O>[I:39][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1/[CH:24]=[C:25]1/[C:26](=[O:37])[C:27]2[C:32]([CH2:33][CH2:34]/1)=[CH:31][C:30]([O:35][CH3:36])=[CH:29][CH:28]=2
Reactant: [I-]
Reactant: COc1ccc2c(c1)CC/C(=C\c1ccncc1Br)C2=O
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CC/C(=C\c1ccncc1I)C2=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
In a Schlenk tube, N,N′-dimethyl-1,2-cyclohexanediamine 85% (32 μL, 0.20 mmol) and dioxane (2 mL) were added to a mixture of CuI (19.2 mg, 0.1 mmol), compound 87 (688 mg, 2.0 mmol) and NaI (600 mg, 4.00 mmol). The Schlenk tube was sealed with a Teflon cap and the reaction mixture was stirred at 110° C. for 24 h. After cooling, the resulting suspension was poured into water (20 mL), and extracted with dichloromethane (3×). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. The product was allowed to crystallize at room temperature. The residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the title compound 88 as a yellow solid (Yield 703.8 mg, 90%).
Reaction SMILES: [NH2:1][CH:2]([C:32]#[N:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.C(N(CC)CC)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:32]#[N:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)C#N)CC4)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)NC(=O)OCc2ccccc2)CC4)CC1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(2-amino-2-cyanoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (800 mg, 1.70 mmol, 1.00 equiv) and triethylamine (340 mg, 3.36 mmol, 2.00 equiv) in dichloromethane (50 mL) was added dropwise a solution of benzyl chloroformate (320 mg, 1.88 mmol, 1.10 equiv) in 10 mL of DCM at 0° C. The resulting solution was stirred for 30 min at this temperature and then quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to give benzyl N-[2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-cyano ethyl]carbamate (0.5 g, 49%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 79%). 1H NMR (200 MHz, CDCl3): δ 3.71 (s, 7H), 4.11 (s, 4H), 6.66 (d, J=9.0 Hz, 2H), 7.10 (m, 1H), 7.22-7.25 (m, 1H), 7.38-7.54 (m, 3H), 7.65-7.68 (m, 1H), 8.19 (d, J=3.8 Hz, 1H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([N:39]4[CH2:38][CH2:37][CH:36]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:41][CH2:40]4)=[CH:43][CH:44]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCOCC5)CC4)cc3)nn12
Yield: 21 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine (0.227 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and The reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 44.36 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=485.8. 1H NMR (400 MHz, DMSO, d6) δ 9.20 (s, 1H), 8.91 (s, 1H), 7.82 (dd, 1H, J=1.56, 6.16 Hz), 7.60 (d, 2H, J=9.01 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.17 Hz), 7.12 (t, 1H, J=7.28 Hz), 6.90 (m, 4H), 4.02 (m, 2H), 3.80 (s, 3H), 3.50 (m, 5H), 3.35 (m, 2H), 3.24 (m, 2H), 2.71 (m, 2H), 2.12 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].O[Li].O>CCO>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)CCBr
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 91 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, condenser, and an Ar inlet was charged with 4-amino-3-nitrophenol (12.0 g, 77.9 mmol), 1-bromo-3-methylbutane (14.7 g, 97.3 mmol), LiOH.H2O (6.55 g, 156 mmol), and EtOH (120 mL). The resultant solution was heated at reflux overnight. Another 3 mL of 1-bromo-3-methylbutane and 1 g of LiOH.H2O were added, and the mixture was heated at reflux overnight again. The solution was cooled and partitioned with EtOAc (250 mL) and H2O (200 mL). The organic phase was washed with 1% aqueous LiOH (2×200 mL), H2O (200 mL), and brine (200 mL), filtered through phase separation paper, and concentrated to a dark red solid. The material was dried to give 15.9 g of 46b as a red solid (91%). 1H NMR (60 MHz, CDCl3): δ 7.2 (d, 1H), 7.0 (dd, 1H), 6.7 (d, 1H), 6.0 (bs, 2H), 3.9 (t, 2H), 1.8-1.4 (m, 3H), 1.0 (d, 6H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 94% with a retention time of 8.6 min.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:2]([C:4]([N:6]([CH3:21])[C@H:7]([C:12](CC1C=CC=CC=1)=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:3].C([OH:31])C>>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:2]([C:4]([N:6]([CH3:21])[C@H:7]([C:12]([OH:13])=[O:31])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:5])[CH3:3]
Reactant: CCO
Reactant: CC(C)C[C@@H](C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
32.45 g (79.92 m mol) BOC-(D)-Ala-MeLeu-Bzl in 800 ml ethanol containing 1.6 g 10% palladium/charcoal are debenzylated by hydrogenation for 2 hours at room temperature. After uptake of the calculated quantity of hydrogen the suspension is filtered through talc, the solvent evaporated off and the residue crystallised from hexane to yield the title compound with a rotation of [α]D25 =-36.7° (c=0.8 in chloroform).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([Cl:30])[CH:8]=1.[CH3:31][C:32]([CH3:55])([CH2:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:30][C:9]1[CH:8]=[C:7]([C:42]2[C:43]([CH3:45])=[CH:44][C:39]([O:38][CH2:37][C:32]([CH3:31])([CH3:55])[C:33]([O:35][CH3:36])=[O:34])=[N:40][CH:41]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
N,N-dimethylformamide (2 mL) was added to 2-(4-bromo-2-chlorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (297 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (228 mg) and palladium chloride (dppf) methylene chloride complex (27 mg), and after adding 2N aqueous sodium carbonate solution (0.98 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 5 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=94:6 to 82:18) to obtain methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (278 mg).