Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33](C(OC(C)(C)C)=O)[CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cn[nH]c2)nc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (235 mg, 0.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (296 mg, 1.0 mmol), tripotassium phosphate (285 mg, 1.3 mmol), S-Phos (27.6 mg, 0.07 mmol), and Pd(OAc)2 (7.5 mg, 0.03 mmol) in THF (3.0 mL) and water (0.5 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.77 (s, 1 H), 8.15-8.13 (m, 2 H), 7.30-7.22 (m, 3 H), 4.50 (dd, J=11.2, 6.9 Hz, 1 H), 4.37 (dd, J=11.3, 7.5 Hz, 1 H), 3.78 (s, 3 H), 3.17 (d, J=5.3 Hz, 1 H), 2.50 (s, 3 H), 2.22 (dt, J=8.5, 4.6 Hz, 1 H), 1.79 (s, 1 H), 1.21-1.16 (m, 1 H), 1.07 (m, 1 H); LRMS m/z (M+H) 338.4 found, 338.2 required.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:29][CH:28]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH:30]3[CH2:31][CH2:32][N:33]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:34][CH2:35]3)=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:17]1[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=[C:15]([NH2:36])[N:16]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC1Cc2ccc(C3CCN(S(C)(=O)=O)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methanesulfonyl chloride. LCMS (M+H)+: m/z=500.3.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:49][CH:48]=2)=CC=1)([O-])=O>>[N:53]1([C:50]2[CH:51]=[CH:52][C:47]([NH:46][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][C:26]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[O:27])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:5])=[CH:48][CH:49]=2)[CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCC(=O)N4CCOCC4)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(COc1ccc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2c1)N1CCOCC1

Procedure:
The title compound was prepared from 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester as synthesized in the previous step, using (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (preparation given in Example 74a), essentially as described in Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.10 (d, 1H), 7.38 (dd, 1H), 7.29 (d, 1H), 7.18 (m, 2H), 6.51 (m, 2H), 6.34 (s, 1H), 4.88 (s, 2H), 4.26 (m, 2H), 3.75-3.61 (m, 7H), 3.55 (m, 2H), 3.25 (m, 4H), 3.10 (td, 2H), 2.16-2.04 (m, 2H), 2.02-1.90 (m, 6H). LC/MS (ESI): calcd mass 544.3, found 545.3 (MH)+.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)nc(CBr)c1
Temperature: 0 °C

Procedure:
A solution of 2,4,6-collidine (1 mmole) in carbon tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide (0.25 mmole) at 80° C. for 12 h. The reaction mixture was cooled to 0° C. and the precipitate was filtered. The filtrate was concentrated under vacuum. Chromatography gave 2-bromomethyl-4,6-dimethylpyridine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:42][OH:43])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:40]#[N:41])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:46])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:42][OH:43])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][S:35](=[O:38])(=[O:39])[CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:40]([NH2:41])=[O:46])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(N6CCS(=O)(=O)CC6)nc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(N6CCS(=O)(=O)CC6)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
In a 25 mL round-bottomed flask, 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (22 mg, 36.6 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1.1 mg, 2.56 μmol, Eq: 0.07) were combined with Ethanol (200 μl) and Water (200 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered and purified by HPLC to obtain 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (15.5 mg, 68%, [M+H]+ 619).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][N:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][N:28]=3)=[CH:21][N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1ccnc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: COc1ccnc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)c1

Procedure:
2-(2-Guanidino-4-thiazolylmethylthio)ethylamine is heated under reflux in pyridine for 12 hours with 0.75 molar equivalents of 2-nitroamino-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone. When this product is boiled under reflux in 2N hydrogen bromide in ethanol 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone trihydrobromide is produced.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7]C[N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([S:30](Cl)(=[O:32])=[O:31])=[CH:27]2)=[CH:22][CH:21]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:7][C@H:3]([NH:2][S:30]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:27]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as in EXAMPLE 24, Part B substituting 3-(3-(S)-Amino-2-oxo-azetidin-1-ylmethyl)benzonitrile hydrochloride for 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride and using 7-methoxynaphthalene-2-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[N:16]=[C:15]([C:17](O)=O)[CH:14]=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[N:16]=[C:15]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1cccc(C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cccc(-c2nc3ccccc3[nH]2)n1

Procedure:
2.2 g. of o-phenylenediamine, 3 g. of 6-ethylpicolinic acid and 15 g. of polyphosphoric acid were heated at 160°-180° C. under a nitrogen gas current for 2 hours with stirring. The reaction mixture was diluted with 200 ml. of water and neutralized with sodium carbonate. The resulting precipitate was filtered off, dried, subjected to silica gel column chromatography(developed with 1:1 by volume mixture of benzene and ethyl acetate) and recrystallized from benzene. 3.3 g. of colorless needles of the product (74% of theory) was obtained. M.P. 161°-161.5° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:19]([N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Cc2c1ccn2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a suspension of 60% sodium hydride (0.17 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of benzoyl chloride (0.59 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 1-benzoyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.78 g).
Reaction SMILES: [CH3:1][C:2]1[C:23]2[CH2:22][C:21]3[C:8](=[CH:9][C:10]4[CH2:11][C:12]5[C:17]([C:18](=O)[C:19]=4[CH:20]=3)=[C:16]([CH3:25])[CH:15]=[CH:14][C:13]=5[CH3:26])[C:7](=O)[C:6]=2[C:5]([CH3:28])=[CH:4][CH:3]=1>COCCOCCOC>[CH3:28][C:5]1[C:6]2[C:23](=[CH:22][C:21]3[C:8]([CH:7]=2)=[CH:9][C:10]2[C:19](=[CH:18][C:17]4[C:12]([CH:11]=2)=[C:13]([CH3:26])[CH:14]=[CH:15][C:16]=4[CH3:25])[CH:20]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c2c1Cc1cc3c(cc1C2=O)Cc1c(C)ccc(C)c1C3=O
Solvent: COCCOCCOC
Product: Cc1ccc(C)c2cc3cc4cc5c(C)ccc(C)c5cc4cc3cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 grams of 7,14-dihydro-1,4,8,11-tetramethylpentacene-5,12-dione and 10 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 0.875 grams of sodium borohydride and stirring was continued at room temperature overnight. To the mixture was added 20 mL of 2-methoxyethyl ether and 0.75 grams of sodium borohydride and heating was continued overnight at 60° C. To the mixture was added 6.3 mL of methanol and 0.75 grams of sodium borohydride and stirring was continued for 6 hours at room temperature. To the mixture was added 15 mL of acetic acid and the mixture was stirred for one hour at room temperature. To the mixture was added 10 mL of concentrated hydrochloric acid and the mixture was heated to 60° C. for 1.5 hours. The solid was isolated by filtration, washed with water and dried to give 1,4,8,11-tetramethylpentacene.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:21]Br.O>CN(C=O)C>[F:16][C:17]([F:30])([F:31])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)[CH2:21][O:13][CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][CH2:10][CH2:9][O:8]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: OCC1(c2ccccc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)OCCO2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
(2-Phenyl-[1,3]dioxolan-2-yl)methanol (14.82 g, 82 mmol) was dissolved in DMF (200 mL) and cooled with ice and sodium hydride (60% oily) (3.60 g, 90 mmol) was added thereto by dividing into two. The mixture was stirred for 1 hour under cooling with ice and for 2 hours at room temperature and then a solution of 3,5-bis(trifluoromethyl)benzyl bromide (16.5 mL, 90 mmol) in DMF (50 mL) was dropped thereinto during 30 minutes under cooling with ice. After the mixture was stirred for 2 hours under cooling with ice and for 20 hours at room temperature, the reaction mixture was added to water followed by extracting with ethyl acetate. The organic layers were combined, washed with a saturated saline solution and dried over anhydrous sodium sulfate. The residual oily product obtained by evaporation of the solvent in vacuo was purified by a silica gel column chromatography (n-hexane:ethyl acetate=19:1) to give 2-(3,5-bis(trifluoromethyl)benzyloxymethyl)-2-phenyl-[1,3]-dioxolane (34.00 g, 100%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.67 (s, 2H), 3.79-3.84 (m, 2H), 4.02-4.08 (m, 2H), 4.74 (s, 2H), 7.31-7.39 (m, 3H), 7.46-7.49 (m, 2H), 7.89 (s, 2H), 7.96 (s, 1H).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])[C:14]=1C#N)#N.CCO.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:1]([O:16][CH2:15][CH3:14])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C=Cc1ccccc1
Yield: 94 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), EtOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with EtOH (10 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Ethyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C2H5) is isolated in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ7.72 (1H, d, J=16.19 Hz), 7.43 (5H, m), 6.47 (1H, d, J=16.19 Hz), 4.28 (2H, q, J=7.09 Hz), 1.34 (3H, t, J=7.09 Hz); 13C-NMR (CDCl3, 75.4 MHz) δ166.9, 144.5, 130.1, 128.8, 128.5, 127.9, 118.2, 60.4, 14.2.
Reaction SMILES: [C:1]1([CH:7]([OH:12])[CH2:8][CH2:9][NH:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.CN1CCCC1=O.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:11][NH:10][CH2:9][CH2:8][CH:7]([O:12][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNCCC(O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Yield: 85 %

Procedure:
An improved process for the preparation in a superior yield of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of formula (I), ##STR5## or a pharmaceutically acceptable acid addition salt thereof, the said process comprising catalytically hydrogenating 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base of formula (II), ##STR6## to obtain 1-phenyl-3-(N-methylamino)-propan-1-ol of formula (III), ##STR7## and selectively etherifying the compound of formula (III) with 1-chloro-4-trifluoromethylbenzene of formula (IV), ##STR8## in a solvent selected from the group consisting of N-methylpyrrolidone and dimethylsulfoxide in the presence of a potassium t-butoxide, whereby N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine is formed in a yield greater than 85 percent of the theoretical value.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.O>O1CCCC1.ClCCl>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[CH:13]
Reactant: COC(=O)c1ccc(N)c(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#Cc1cc(C(=O)OC)ccc1N
Yield: 100.1 %

Procedure:
1.9 g (7.7 mmol) of methyl 4-amino-3-trimethylsilylethynylbenzoate were initially charged in 20 ml of tetrahydrofuran (THF). At from 5° C. to 8° C., 8.45 ml (8.5 mmol) of tetrabutylammonium fluoride solution (1 M in THF) were added dropwise within 5 minutes. After 25 mm at 2° C., 438 ml of acetic acid were added. After addition of water and extraction with dichloromethane, and after removal of the solvent, 1.35 g of methyl 4-amino-3-ethynylbenzoate were obtained. HPLC method as in example 1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[O:13][CH3:14].[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>>[Cl:5][C:6]1[CH:11]=[C:10]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:8]([F:12])[C:7]=1[O:13][CH3:14]
Reactant: COc1c(F)cccc1Cl
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1cc(F)c(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
Aluminum chloride (1.16 g, 8.72 mmol) was added to a stirred mixture of 1-chloro-3-fluoro-2-methoxybenzene (1.00 mL, 8.72 mmol) and hexanoyl chloride (1.47 mL, 10.46 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 67 hours and then partitioned between EtOAc (40 mL) and ice cold water (40 mL). The EtOAc layer was washed with brine (30 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone as an oil.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: COc1ccc(OC)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cc(OC)ccc4OC)cc32)n1

Procedure:
Tert-butyl 4-[6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (203 mg, compound B101), (2,5-dimethoxyphenyl)boronic acid (100 mg), dichlorobis(tricyclohexylphosphine)palladium (37 mg) and aqueous cesium carbonate solution (0.375 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: [O:1]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[Mg][CH2:10][CH:11]1[CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[CH:11]1([CH2:10][CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C=O
Reactant: Br[Mg]CC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)CC1CC1
Reaction time: 48 h

Procedure:
Under argon and with ice cooling, a solution of 5.4 g (purity 50%, 26.7 mmol) of ethyl oxoacetate in 50 ml of THF was quickly added dropwise to 7.6 g (48 mmol, 1.8 eq.) of bromo(cyclopropylmethyl)magnesium. The reaction mixture was stirred for another 48 h, diluted with ethyl acetate and quenched with water. Celite was added, and the reaction mixture was stirred for 5 min and then filtered. After phase separation, the organic phase was washed once with water, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 2.6 g (60% of theory)
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4]([F:22])[CH:3]=1.[Li]CCCC.[NH4+].[Cl-].[BH4-].[Na+].[C:32]([O-])(O)=[O:33].[Na+]>CO.CN(C=O)C.C1COCC1>[F:22][C:4]1[CH:3]=[C:2]([CH2:32][OH:33])[CH:21]=[CH:20][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CO)cc2F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a THF (44 mL) solution of tert-butyl 4-(4-bromo-2-fluorobenzyl)piperazine-1-carboxylate (8.445 g) was added slowly n-BuLi (11.31 mL, 2.6 M in hexane) at −78° C., then the resultant mixture was stirred for 0.5 hour. To the mixture was added slowly DMF (1.927 mL) at −78° C. After stirring for 1 hour at −78° C., then the mixture was stirred at room temperature over night. The mixture was poured into saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 2/1) to afford a colorless oil. To a MeOH (13 mL) solution of that colorless oil was added NaBH4 (0.200 g) at 0° C., then the resultant mixture was stirred for 5 hours. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/1) to afford tert-butyl 4-[2-fluoro-4-(hydroxymethyl)benzyl]piperazine-1-carboxylate as a colorless oil (0.500 g).