Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.S(Cl)(Cl)=O.[NH3:20]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:20])=[O:12])=[N:9][CH:10]=1
Reactant: N
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 50 °C

Procedure:
20 g of 5-(3,4-dibromobutyl)picolinic acid was added to 15 ml of thionyl chloride and resulting solution was kept to warm at 50°C for one-half hour. Reaction mixture was evaporated in reduced pressure and resulting oily residue was dissolved in chloroform 100 ml. Through the solution dry ammonia gas was passed for five minutes with cooling. White precipitate was removed by filtration and washed with chloroform. Filtrate and washings are combined and evaporated in reduced pressure. Resulting solid was crystallized from benzene to give 10.2 g of the pure product as platelets.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:9][CH2:10]Cl)[C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([N:19]1[CH2:10][CH2:9][N:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)N(CCCl)CCCl
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(C)(C)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 2000 g of bis-(2-chloroethyl)-tert-butylamine in 500 cc of ethanol and a solution of 1095 g of benzylamine in 750 cc of ethanol are simultaneously added dropwise to 1000 cc of boiling ethanol. After the addition is complete, the reaction mixture is heated to the boil for 1 hour. The mixture is subsequently concentrated in a vacuum and the residue is dissolved in dilute hydrochloric acid. The acid solution is washed with ether and is subsequently rendered alkaline with a concentrated, aqueous sodium hydroxide solution. The liberated base is extracted with ether and the ether residue is distilled. 1-benzyl-4-tert-butyl piperazine has a B.P. of 160°-162° at 12 mm of Hg.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[N:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:11](/[C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[N:7][CH:8]=1)=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncc(/C=C/c2ccccc2)c1
Reaction time: 3 h

Procedure:
Add a solution of commercially available 5-phenylethynyl-nicotinic acid ethyl ester (0.4 g, 1.59 mmol) in dry tetrahydrofuran (20 mL) to a solution of lithium aluminum hydride (20 mL, 0.08 M in tetrahydrofuran) at room temperature under nitrogen and stir for 3 h. Add a solution of lithium aluminum hydride (2 mL, 1 M in tetrahydrofuran) and stir for 1 h. Slowly add methanol (2 mL) and concentrate. Dilute with ethyl acetate, wash with water and a saturated aqueous solution of sodium chloride and dry. Purify the residue by silica gel chromatography, eluting with 5:1 hexanes:ethyl acetate to 10:90 hexanes:ethyl acetate, to give the E-isomer (7 mg, 2%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1C
Solvent: CC#N
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 107.2 %

Procedure:
A mixture of methyl 3-bromo-2-methylbenzoate (17.0 g, 74.22 mmol) and N-bromosuccinimide (15.85 g, 89.06 mmol) in acetonitrile (200 mL) was heated under gently refluxing for 17 hours while a 200 W bulb situated 2 cm away was shining on the reaction flask. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in ethyl acetate (200 mL) and washed with water (3×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-bromomethylbenzoate (24.5 g, 97% by HPLC): 1H NMR (CDCl3) δ 7.90–7.86 (dd, J=1.0 and 7.9 Hz, 1H), 7.78–7.74 (dd, J=1.2 and 8.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]3[C:15]=2[CH2:16][NH:17][C:18](=[O:34])[N:19]3[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCOCC>Cl.C(O)C>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=2)[CH2:16][NH:17][C:18]1=[O:34]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)N(Cc1cccc(F)c1)C(=O)NC2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(N2CCNCC2)c2c(c1)N(Cc1cccc(F)c1)C(=O)NC2
Temperature: 80 °C

Procedure:
4-[1-(3-Fluoro-benzyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (43 mg) was dissolved in 4 mL 2N HCl/ethanol and heated to 80° C. for 20 minutes. The reaction mixture was cooled to room temperature, and ether was added, precipitating 18 mg of 1-(3-fluoro-benzyl)-7-methoxy-5-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one. MS: 371 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:26])[C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid XXI (1 g, 3 mmol) in dry THF (10 mL) was added sodium hydride (60% suspension in mineral oil) (0.72 g, 18 mmol; 6 eq. of pure NaH) in portions. Methyl iodide (1.12 mL, 18 mmol) was then added and the mixture was stirring at r.t. for 3 days. The mixture was then treated with water before removing the THF under reduced pressure. The aqueous phase was acidified and extracted 2× EtOAc. The combined EtOAc was washed with sodium thiosulfate, dried and evaporated under reduced pressure. The residue was crystallized to produce (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[4-(trifluoromethyl)phenyl]-propanoic acid XXII (0.73 g, 2 mmol, 70% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([CH2:55][OH:56])=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[C:39]([CH2:55][OH:56])[N:37]5[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(CO)n2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and (6-Fluoro-1-tributylstannanyl-imidazo[1,5-a]pyridin-3-yl)-methanol (crude from Step 5) were dissolved in DMF (2 ml The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h then cooled to room temperature, quenched with water and extracted with dichloromethane (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 83 mg (71%) of 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][NH:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=O)[CH:4]=1)#[N:2].CC([O-])(C)C.[K+].Cl>CCO>[OH:15][C:13]1[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C=C/NNc1cc(C#N)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccnc(-n2nccc2O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of ethyl (2E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]prop-2-enoate (2.0 g, 8.62 mmol) in 30 mL EtOH was added t-BuOK (1.93 g, 17.24 mmol) at 0-5° C. The mixture was stirred for 3 days at rt. The mixture was adjusted to pH=6 with 1 N HCl with cooling. The mixture was extracted with EtOAc (3×100 mL). The organic layers were washed with 200 ml brine, dried over Na2SO4, and concentrated to dryness. The resultant residue was stirred with PE/EtOAc (10/10 mL) for 30 min and filtered to give the title compound (500 mg, 31%) as a red solid. 1H NMR (400 MHz, CDCl3): δ 4.63 (1H, s), 7.12 (1H, dd, J=4.8, 1.2 Hz), 7.16 (1H, s), 8.35 (1H, d, J=4.4 Hz), 8.43 (1H, s). [M+H] Calc'd for C9H6N4O, 187; Found, 187.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:23]([O-])([O-:25])=[O:24].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:23]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:7][CH:6]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1ccc(Cc2ccccc2)cn1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.0 Grams of methyl 5-benzylpicolinate were dissolved in 20 ml. of concentrated sulfuric acid at room temperature. A solution of 2.7 g of sodium nitrate in 20 ml. of concentrated sulfuric acid was added dropwise thereto under cooling to keep internal temperature at 5° C. After three hours, the reaction solution was poured into ice-water and neutralized with sodium carbonate. After extraction with ethyl acetate, washing with water and drying, the solvent was distilled out. The residue was recrystallized from methanol to obtain 3.5 g of 172°-178° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (4.76 g, 30 mmol) and 3-amino-4-chlorophenol (4.31 g, 30 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.15 g, 30 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate (80 mL), and the mixture was washed successively with water (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate (15 mL)/n-hexane (15 mL), and the precipitated crystals were collected by filtration, washed with diisopropyl ether (20 mL), and dried under reduced pressure to give the title compound (6.74 g, 85%) as brown crystals.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][C:11]([O:13]CC(C1C=CC(Br)=CC=1)=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:1]([O:8][C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCCCCCCCC[C@H](CC(=O)OCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Zinc dust (<10 micron, 382 mg, 5.87 mmol) was added portionwise to a solution of 117 (320 mg, 0.587 mmol) in acetic acid (15 mL). The reaction mixture was stirred at 60° C. for 2 h and then diluted with DCM (20 mL). The solids were filtered off through a pad of Celite and the residue was washed with DCM (3×5 mL). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: DCM/methanol, 100/1, v/v) to afford 107 as an amorphous solid (198 mg, 97%). Rf=0.40 (toluene/ethyl acetate, 3/1, v/v); [α]25D=−2.3° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.35-7.25 (m, 5H, aromatic), 4.55 (s, 2H, CH2Ph), 3.86 (m, 1H, H-3), 2.62 (dd, 1H, J2a,2b=15.6 Hz, J2a,3=6.9 Hz, H-2a), 2.53 (dd, 1H, J2a,2b=15.6 Hz, J2b,3=5.1 Hz, H-2b), 1.66-1.45 (m, 3H, H-4, H-13), 1.38-1.10 [m, 16H, H-(5-12)], 0.85 (d, 6H, J15,16=6.9 Hz, H-14); 13C NMR (75 MHz, CDCl3): δ 176.76 (C═O), 138.04-127.73 (aromatic), 75.70 (C-3), 71.53 (CH2Ph), 39.42 (C-2), 39.03 (C-12), 34.09 (C-4), 22.66 (C-14); HR MS (m/z) calculated for C22H36O3 [M Na]+, 371.2557; found, 371.1906.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][CH3:13])[C:4]=2[C:3]=1[C:14]([F:17])([F:16])[F:15].[H][H]>CO.[Pd]>[CH3:13][NH:12][CH2:11][CH:5]1[C:4]2[C:3]([C:14]([F:17])([F:15])[F:16])=[CH:2][S:10][C:9]=2[CH2:8][CH2:7][O:6]1
Reactant: CNCC1OCCc2sc(Br)c(C(F)(F)F)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNCC1OCCc2scc(C(F)(F)F)c21

Procedure:
To a solution of 1-(2-bromo-3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylmethanamine (5 mmol) in MeOH (5 mL) was added a catalytic amount of Pd/C. A vacuum was applied and the reaction vessel was back filled with hydrogen gas three times. The resulting mixture was stirred under atmospheric H2. After the reduction was completed, the reaction mixture was filtered and the filter cake was washed with methanol. The combined filtrate was concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]=[CH:22][NH:23]O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1>[OH-].[K+]>[Br:1][C:2]1[C:3]2[N:4]([N:23]=[CH:22][N:21]=2)[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N=CNO)n2)CC1
Agent: [K+]
Agent: [OH-]
Product: Brc1cnc(N2CCNCC2)n2ncnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-4-(((hydroxyamino)methylene)amino)pyrimidin-2-yl)piperazine-1-carboxylate (1.1 g) and polyphosphoric acid (20 g). The resulting mixture was stirred at 100° C. overnight. Work-up: the reaction mixture was carefully diluted with saturated aqueous KOH (300 mL) and then extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 0.3 g (39%) of the product as a white solid. MS m/z: 283 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])=[CH:17][CH:16]=1)=[O:22]
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 32.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.023 g (33%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 2-(4-chlorophenyl)ethanol (2.00 g, 12.77 mmol) in dichloromethane (100 ml) was added Dess-Martin periodinane (8.12 g, 19.16 mmol) and the mixture was stirred at room temperature over weekend. Then was added diethylether (150 ml) and the resulting mixture was washed with a 1:1 solution (150 ml) of sodium carbonate (aqueous saturated) and sodium thiosulfate (aqueous saturated) and then with sodium bicarbonate (aqueous saturated) and finally with brine. The organic phase was then dried over sodium sulfate and evaporated. Silica gel flash chromatography (pentan/ethylacetate:9/1) afforded the desired compound (0.834 g, 42%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([O:11]C)=O)=[C:7]([OH:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1(=[O:19])=[O:18])[CH3:2].[NH2:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1>C1(C)C(C)=CC=CC=1>[Cl:27][C:23]1[N:22]=[C:21]([NH:20][C:9]([C:8]2[N:3]([CH2:1][CH3:2])[S:4](=[O:19])(=[O:18])[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=3[C:7]=2[OH:13])=[O:11])[CH:26]=[N:25][CH:24]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCN1C(C(=O)OC)=C(O)c2ccccc2S1(=O)=O
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Yield: 63.9 %

Procedure:
8.5 g (30 mmols) of methyl 2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 3.9 g (30 mmols) of 2-amino-6-chloro-pyrazine were reacted in 600 ml of xylene and worked up analogous to Example 1, yielding 7.3 g (64% of theory) of N-(6-chloro-pyrazin-2-yl)-2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][CH:2]1[CH:7]=[C:8]([CH3:9])[O:10][C:4](=[O:6])[CH2:3]1
Reactant: CC(=O)CC(C)CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1=CC(C)CC(=O)O1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A solution of 3-methyl-5-oxohexanoic acid (2.1 g) in benzene (26 mL) was treated at rt with thionyl chloride (1.26 mL). The mixture was heated to 85° C. where it stirred for 2 days. At the conclusion of this period, the mixture was cooled to rt and concentrated under vacuum to provide 4,6-dimethyl-3,4-dihydropyran-2-one as a dark brown oil, which was used directly in Step 4 without purification. Mass spectrum m/z 127.37 (M+H+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][CH:26]=[CH:25]2)=[CH:20][CH:19]=1)=[O:17].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:25]=[CH:26][N:27]=[CH:28]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a THF (5 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane (0.178 g, 1.1 mmol) was added n-butyl lithum (1.6 M solution in hexane, 0.72 mL, 1.2 mmol) at 0° C. under nitrogen, and the mixture was stirred for 30 minutes, and cooled to −78° C. 4-(1-Imidazolyl)acetophenone (prepared according the method of M. A. Khan et. al., J. Chem. Soc. C., 1970, 85., 0.186 g, 1.0 mmol) was added to the mixture, and residue was stirred for 1 hour. Ethyl trifluoroacetate (0.17 g, 1.2 mmol) was added to the reaction mixture, the residure was warm to room temperature. The reaction mixture was poured into ice water and the whole was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting solid was washed with small amount of ethyl acetate to give the title compound (0.163 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N:36]1([CH2:45][CH2:46][C:47](O)=[O:48])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:47](=[O:48])[CH2:46][CH2:45][N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)[CH2:8][CH2:7]1
Reactant: O=C(O)CCn1ccc2ccccc21
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCn2ccc3ccccc32)CC1
Reaction time: 48 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (465 mg, 2.0 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (830 mg, 3 mmol.) was added to a solution of 3-indol-1-ylpropionic acid (383 mg, 2.0 mmol.) in abs. methanol (35 ml), and stirring was carried out for 2 d at RT. For working up, the mixture was concentrated, water (15 ml) was added to the residue, the pH was adjusted to 11 with 5M NaOH and extraction was carried out with EE (4×15 ml). The combined extracts were dried, filtered and concentrated. A mixture of the diastereoisomeric bases of the target product was obtained as the residue and was separated by flash chromatography on silica gel (70 g) and purified (eluant: 1300 ml of methanol/EE 1:1). 254 mg of the non-polar diastereoisomer of N-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-indol-1-ylpropionamide were obtained in the form of a viscous oil. 226 mg (0.56 mmol.) thereof were dissolved in abs. ethanol (3 ml) and added dropwise at RT, with stirring, to citric acid (108 mg, 0.56 mmol.) dissolved in hot ethanol (1 ml). After stirring for 1 h at RT, the white precipitate that had formed was filtered off with suction, washed with cold ethanol (1 ml) and with diethyl ether (3×1 ml) and dried in vacuo. 262 mg of the corresponding citrate were obtained (light-beige solid, m.p. 192–194° C.).