Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])[C:2]#[CH:3].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[CH3:13][O:14][CH2:15][C:16]([N:4]([CH2:1][C:2]#[CH:3])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=[O:17]
Reactant: C#CCNc1c(C)cccc1C
Reactant: COCC(=O)Cl
Solvent: Cc1ccccc1
Product: C#CCN(C(=O)COC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A mixture of 3.18 g (0.02 mole) of N-(2-propynyl)-2,6-dimethylbenzenamine, 2.4 g (0.022 mole) of methoxyacetyl chloride and 6 g of 4A molecular sieves in 100 ml of toluene is stirred at 60° overnight under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and then filtered. The filtrate is combined with 200 ml of ether and washed with water, saturated sodium chloride solution, and dried over sodium sulfate. The drying agent is filtered and the solvent is evaporated under vacuum to give an orange-red oily material which is further purified by column chromatography (silica gel) using 20/80 ethyl acetate-n-hexane as solvent to give 2.57 g of pure product.
Reaction SMILES: [CH:1]1([C:7](=[O:22])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[O:32]>C1COCC1>[CH2:35]([O:34][C:30](=[O:33])[CH:31]([OH:32])[CH:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:13][CH:14]=1)[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:22])[CH3:36]
Reactant: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCCCC1
Reactant: CCOC(=O)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)C(C(=O)C1CCCCC1)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
To a stirred solution of 1-cyclohexyl-2-(4-cyclohexyloxy-phenyl)-ethanone (1.17 mmol, 0.35 g) and triethylamine (1.17 mmol, 0.16 mL) in THF (1.0 mL) was added a solution of ethyl glyoxylate (50% in toluene, 5.83 mmol, 1.15 mL) and continued stirring for 12 h at room temperature. After removal of volatiles under reduced pressure, the crude product was purified on a 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 4-cyclohexyl-3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-butyric acid ethyl ester (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][C:15](OCC)=[N:14][CH2:13][CH2:12]1)=[O:10].[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([NH:28][NH2:29])=O>C(O)CCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]2[C:26]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][N:20]=3)=[N:28][N:29]=[C:15]2[CH2:16]1)=[O:10]
Reactant: NNC(=O)c1cnccn1
Reactant: CCOC1=NCCN(C(=O)c2cccc(Cl)c2Cl)C1
Solvent: CCCCO
Product: O=C(c1cccc(Cl)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-[(2,3-dichlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.48 g, 1.594 mmol, e.g. prepared as described below) and 2-pyrazinecarbohydrazide (0.242 g, 1.753 mmol, CAS [768-05-8], commercially available e.g. from TimTec, J & W PharmLab or AKos Consulting) in anhydrous n-butanol (3.19 ml) was heated to reflux under argon atmosphere. After 2 hours the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by mass-directed automated (preparative) HPLC (MDAP) to give pure 7-[(2,3-dichlorophenyl)carbonyl]-3-(2-pyrazinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.260 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]([OH:19])[CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CCOCC.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.C(O)C.O.C1(C)C=CC=CC=1>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]([OH:19])[CH2:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O[C@@H](CCc1ccc(Br)cc1)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: O[C@@H](CCc1ccc(-c2cccc(Cl)c2)cc1)CCc1cccnc1
Temperature: 100 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), water (1 ml), (3S)-1-(4-bromophenyl)-5-(3-pyridyl)-3-pentanol (0.09 g), sodium carbonate (0.172 g), 3-chlorobenzeneboronic acid (0.05 g), ethanol (1 ml) and tetrakis(triphenylphosphine)palladium(0) (9 mg) with heating at 100° C. for 45 minutes. After work up the residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil which was converted to the oxalate salt upon treatment with oxalic acid (excess) in ether to give the title compound as a solid (0.057 g).
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][N:25](CC3C=CC=CC=3)[N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][NH:25][N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1)C(=O)NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nn[nH]n1)C(=O)NS(C)(=O)=O
Reaction time: 2 h

Procedure:
Next, A solution of 2-benzyl-2H-tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide in MeOH/EtOAc is hydrogenated under H2 baloon by catalyst 10% Pd/C wet for 2 hours. The reaction is filtered off the catalyst and is concentrated. Reverse phase HPLC [35 to 80% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18 column] provides 2H-Tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J=7.1 Hz, 2H), 1.66 (ddd, J=13.8, 10.9, 3.5 Hz, 1H), 1.91 (ddd, J=13.7, 10.7, 3.4 Hz, 1H), 2.54-2.63 (m, 1H), 2.79-2.86 (m, 1H), 2.86-2.93 (m, 1H), 3.24 (s, 3H), 4.15-4.28 (m, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.30-7.36 (m, 1H), 7.43 (t, J=7.6 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.59-7.65 (m, 2H), 9.19 (br. s., 1H), 11.54 (br. s., 1H). HPLC retention time=1.24 min (method C): MS (m+1)=457.1.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1c(Cl)cncc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2oc(-c3c(Cl)cncc3Cl)nc2c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 0.35 g of 3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide, 5 ml of carbon tetrachloride, 0.78 g of triphenylphosphine and 0.30 g of triethylamine was heated to reflux for three hours. The mixture was cooled to room temperature, and then water was added to the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3,5-dichloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 17”).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:9][C:10]=1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])C.[OH-].[Li+]>C1COCC1.C(O)C>[C:15]([O:14][C:12]([NH:11][C:10]1[S:9][C:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:7][C:6]=1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid ethyl ester (151 mg, 0.43 mmol) in a THF/ethanol mixture (3 ml; 2:1) was cooled to 0° C. and treated with lithium hydroxide (1.3 ml; 1N aqueous solution). After 15 min, the cooling bath was removed and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was acidified with HCl (1.3 ml, 1N aqueous solution) and extracted with dichloromethane (2×10 ml). The combined organic layers were dried and the solvent was evaporated to yield the product as off-white solid (143 mg, 100%) which was used without any further purification.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[N:21](COCC)[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl.C(Cl)Cl>[C:33]1([CH2:32][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[NH:21][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOCn1c(CCCCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCCCCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Yield: 92.4 %

Procedure:
A suspension of N,N-bis(phenylmethyl)-2-(5-chloropentyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 3 mmole) in 6N hydrochloric acid (100 mL) was heated at reflux for 1 hour. The reaction mixture was cooled, diluted with methylene chloride, made basic with 10% sodium hydroxide and then extracted with methylene chloride (400 mL total). The methylene chloride extracts were combined, dried over magnesium sulfate and then concentrated under vacuum to provide about 1.3 g of N,N-bis(phenylmethyl)-2-(5-chloropentyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCCCC(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A solution of 1-benzyl-3-(tritylamino)-2-azepanone (425 mg, 0.922 mmol) in tetrahydrofuran (11 ml) was added dropwise to a suspension of lithium aluminum hydride (140 mg, 3.69 mmol) in tetrahydrofuran (22 ml) at room temperature, and the resulting mixture was stirred for 30 minutes and then refluxed for 3 hours. After the reaction mixture was cooled, water (0.14 ml), a 2N-aqueous sodium hydroxide solution (0.3 ml) and water (0.14 ml) were added thereto under ice-cooling. The resulting mixture was filtered and the solvent of the filtrate was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 1-benzyl-N-trityl-3-azepanamine (319 mg, 78%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O-:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].COCCOCCN(CCOCCOC)CCOCCOC>COCCOCCOC.[Cu]Cl>[CH:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C([O-])c1ccccc1Cl
Reactant: [O-]c1ccccc1C1CCCCC1
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)c1ccccc1Oc1ccccc1C1CCCCC1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 21.4 g (0.12 mol) of sodium 2-chlorobenzoate, 26.1 g (0.132 mol) of sodium 2-cyclohexylphenolate, 4.95 g (0.05 mol) of copper(I) chloride and 16.17 g (0.05 mol) of tris[2-(2-methoxyethoxy)-ethyl]amine (TDA) in 1.5 l of diethylene glycol dimethyl ether ("diglyme") is kept at 140° C. for 8 hours. The solvent is then concentrated on a vacuum rotary evaporator and the residue is diluted with water and acidified with concentrated hydrochloric acid. The product is extracted with ethyl acetate. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. 22.2 g (68%) of 2-(2-cyclohexylphenoxy)benzoic acid, melting point 109°-123° C., result as a beige powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2C=O)c1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2,5-difluorobenzaldehyde (0.80 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.35 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[O:19][C:20]([F:23])([F:22])[F:21])(=[O:11])=[O:10])[CH2:4][CH2:3]1.Cl[C:25]1[N:34]=[C:33]([N:35]([CH3:37])[CH3:36])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CC(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:25]3[N:34]=[C:33]([N:35]([CH3:37])[CH3:36])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH2:3][CH2:4]2)(=[O:11])=[O:10])=[C:13]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=1
Reactant: N[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Solvent: CC(C)O
Product: CN(C)c1nc(N[C@H]2CC[C@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12

Procedure:
To a solution of trans-N-(4-amino-cyclohexyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamide (100 mg, 0.24 mmol) in 2-propanol (0.5 mL) was added (2-chloro-quinazolin-4-yl)-dimethly-amine obtained in step B of example 1 (54.7 mg, 0.26 mmol). The mixture was heated using a Smith Microwave Synthesizer at 170° C. for 15 min. The mixture was concentrated and the residue was purified by chromatography (2% to 4% 2 M NH3/MeOH in CH2Cl2) to give trans-4-bromo-N-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide (42 mg, 0.71 mmol, 30%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:55][C@H:54]([CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=1)[CH2:56][NH:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)c3c[nH]c4ccccc34)CC2)cc1
Product: O=C(c1c[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(1H-indol-3-yl)methanone (Step C) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.20 g, 0.495 mmol) according to Procedure G to give the title compound (0.03 g, 0.057 mmol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:14]1
Reactant: COc1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 35 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-methoxyphenyl)piperidin-1-yl]-methanone (21 mg, 0.059 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 7.0 mg of the title compound.
Reaction SMILES: [C:1](=[O:15])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])[O:2][CH2:3]Cl.[C:16]([O-:20])(=[O:19])[CH:17]=[CH2:18].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:15])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])[O:2][CH2:3][O:20][C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=O)OCCCCOC(=O)OCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OCOC(=O)C=C
Yield: 91.1 %

Procedure:
Chloromethyl 4-acryloyloxybutyl carbonate (1.183 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.24 g (91%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.82 (4 H, m, CH2 --CH2), 4.23 (4 H, m, 2×CH2 --O), 5.88 (2 H, s, O--CH2 --O), 5.7-6.8 (6 H, 2×CH=CH2).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenylboronic acid (2.2 g, 8.5 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.79 g, 10.2 mmol), Pd(PPh3)2Cl2 (179 mg, 0.26 mmol), K2CO3 (2.35 g, 17 mmol), and Cu2O (37 mg, 0.26 mmol) in THF (6 mL) and H2O (3 mL) in a tube sealed under N2 was heated at 80° C. for 4 h, cooled to rt and partitioned between EA and water, extracted with EA (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE to afford 1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.5 g, yield 55%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C21H23ClN6O2, 410.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[C:5]([O:27][CH3:28])[C:4]=1B(O)O.[CH2:32]([O:34][C:35](=[O:56])[C@H:36]([CH2:48][C:49]1[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=1)[NH:37][C:38](=[O:47])[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:46])[CH3:33].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[CH2:32]([O:34][C:35](=[O:56])[C@H:36]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:4]2[C:5]([O:27][CH3:28])=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:51][CH:50]=1)[NH:37][C:38](=[O:47])[C:39]1[C:40]([Cl:46])=[CH:41][CH:42]=[CH:43][C:44]=1[Cl:45])[CH3:33]
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(O)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of 2,6-dimethoxy-4-(tert-butyl-diphenylsilyloxy)benzeneboronic acid (3 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (0.8 g), Pd(PPh3)4 (1 g) and K2CO3 (2.1 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 6 hour under N2. The mixture was diluted with EtOAc and washed with water, dried and evaporated. The residue was dissolved in EtOAc and the solution was filtered through a silica gel column and evaporated. The residue was dissolved in THF, and TBAF (1.6 M in THF, 4 ml) was added. The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with EtOAc. The extract was washed with water, dried and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1/2) to yield 0.5 g of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-4-hydroxyphenyl)-L-phenylalanine ethyl ester. ESMS m/z: 490 (MH+).