Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3C[CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:29])[CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(=O)c1cccc(OCCCCl)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCOc3cccc(C(C)=O)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(3-chloropropoxy)phenyl]ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 421.2 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][N:13]2[N:12]=1.[N:21]1([C:25]([C:27]2[CH:31]=[N:30][N:29]([CH3:32])[C:28]=2[C:33](O)=[O:34])=[O:26])[CH2:24][CH2:23][CH2:22]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH:19][C:33]([C:28]3[N:29]([CH3:32])[N:30]=[CH:31][C:27]=3[C:25]([N:21]3[CH2:24][CH2:23][CH2:22]3)=[O:26])=[O:34])[CH:17]=[CH:18][N:13]2[N:12]=1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3OCCF)nc2c1

Procedure:
This compound was prepared in analogy to 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-dimethylamide 3-({2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide) (Example 100) from 2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (127 mg, 0.47 mmol) and 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (130 mg, 0.62 mmol). Yield: 95 mg (33%); off-white solid; LC-MS: m/z=464.2 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(NC(C)C)(C)C>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.[Cu]I.C1COCC1>[N:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 57 °C
Yield: 99.8 %

Procedure:
To a mixture under Ar of (4-iodo-phenyl)-morpholin-4-yl-methanone (273 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields 247 mg of morpholin-4-yl-(4-trimethylsilanylethynyl-phenyl)-methanone as a light brown solid, 1H-NMR (300 MHz): 0.26 (s, 3H); 3.32-3.91 (br, 8H); 7.34 (d, J=6.5, 2H); 7.51 (d, J=6.5, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20](O)(=[O:30])[CH2:21][CH2:22][CH2:23]CCCCCC.[CH2:32]([O:36][CH2:37][CH:38]=[CH:39][CH3:40])[CH2:33][CH2:34][CH3:35].[CH2:41]([OH:45])[CH2:42][CH2:43][CH3:44].O>>[CH:20](=[O:30])[CH2:21][CH2:22][CH3:23].[CH2:37]([O:36][CH:32]([O:45][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:33][CH2:34][CH3:35])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCO
Reactant: CC=CCOCCCC
Reactant: CCCCCCCCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCCC=O
Product: CCCCOC(CCC)OCCCC
Temperature: 155 °C
Reaction time: 8 h

Procedure:
A glass autoclave was filled with 0.022 g of the catalyst HRuCl(CO)(PPh3)3, 0.031 g of triphenylphosphine, 0.005 g of decanoic acid, 3.18 g (24.8 mmol) of 1-butoxybut-2-ene and 1.83 g (24.8 mmol) of n-butanol and stirred for 8 hours under autogeneous pressure at 155° C. Thereafter, 2.2 g (122 mmol) of water were added and stirring was continued for a further hour at 155° C. The reaction mixture was analyzed by means of calibrated gas chromatography. At a conversion of 99%, n-butyraldehyde was obtained with a selectivity of 80% and 1,1-dibutoxybutane with a selectivity of 9%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.P([C:22]#[N:23])(=O)(OCC)OCC.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([O:31][N:32]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])[CH2:27][CH2:26]1.C(N(CC)CC)C>O1CCCC1>[O:41]=[C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:42])[N:32]1[O:31][CH:28]1[CH2:29][CH2:30][N:25]([CH:8]([C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[C:22]#[N:23])[CH2:26][CH2:27]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
4-(Trifluoromethoxy)benzaldehyde (0.342 ml, 2.39 mmol) was added to a solution of diethyl phosphorocyanidate (0.363 ml, 2.39 mmol) in tetrahydrofuran (12 ml) and stirred at room temperature for 10 minutes. A suspension of 2-(piperidin-4-yloxy)isoindoline-1,3-dione hydrochloride (564 mg, 2.00 mmol) and triethylamine (0.332 ml, 2.39 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture, and the whole was stirred at room temperature for 24 hours and at 60° C. for 17 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexane: 5/95 to 25/75) to give 2-(4-(1,3-dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (261 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30].[H-].[Na+].[CH2:39](Br)[C:40]#[CH:41].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:15]([F:16])([F:18])[F:17])=[O:12])[N:8]2[CH2:41][C:40]#[CH:39])=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30]
Reactant: C#CCBr
Reactant: N#CC1(NC(=O)c2cc3cc(C(=O)NC(c4cccc(C(F)(F)F)c4)C(F)(F)F)[nH]c3cc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Yield: 50.9 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.14 g, 0.26 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (1 ml). Sodium hydride (60%; 0.079 g, 1.97 mmol) was added and the mixture was stirred while cooling with ice for 1.5 h. Subsequently, propargyl bromide (0.04 mg, 0.26 mmol) was added dropwise. The reaction mixture was thawed while stirring within 16 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.075 g (50% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-1-(prop-2-yn-1-yl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]([N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[CH3:19][N:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][NH2:8]
Reactant: CN(C(=O)CN)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)c1ccncc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
2-Amino-N-methyl-N-pyridin-4-yl-acetamide trifluoroacetate (182, 1.0 eq.) was dissolved in anhydrous THF (50 mL) under argon. A 1 M solution of LiAlH4 in THF (6.1 eq.) was added dropwise at rt and the reaction vessel was placed in an oil bath. The temperature was raised to 70° C. and the mixture stirred for 15 hr. The reaction mixture was cooled and quenched by the slow addition of water (5 mL). Solvents were evaporated to give a white solid which was titurated several times with ethyl acetate to give compound 183 as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][CH:5]([CH2:8][CH2:9]O)[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:32][CH2:9][CH2:8][CH:5]1[CH2:6][O:7][C:2]([CH3:11])([CH3:1])[O:3][CH2:4]1
Reactant: CC1(C)OCC(CCO)CO1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C

Procedure:
To a solution of compound 32 (84 g, 0.528 mol) in dry DMF (500 mL) was added triphenylphosphine (207 g, 0.79 mol) with vigorous stirring until it becomes a clear solution. The mixture was cooled to 0° C. and added CBr4 (260 g, 0.79 mol) portion wise over a period of 30 min and allowed to stir at RT for 5 h. The reaction mixture was cooled to 0° C., added saturated NaHCO3 solution (200 mL) and extracted with hexane (4×200 mL). The combined organic layer was dried, concentrated under vacuum and the crude title compound (117 g) was used for next reaction without any purification. TLC: Pet. ether/EtOAc, 7:3, Rf=0.6
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][N:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12]1
Reactant: ClCC=Cc1ccccc1Cl
Reactant: c1ccc2c(c1)CNC2
Solvent: CCO
Product: Cl
Product: Clc1ccccc1C=CCN1Cc2ccccc2C1
Yield: 41 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 3.46 grams of o-chlorocinnamyl chloride and 4.41 grams of isoindoline in 20 milliliters of ethanol is stirred for 12 hours at room temperature. After cmmpletion of the reaction, the solvent is distilled off. The resulting residue is then rendered alkaline by the addition of 10% sodium hydroxide and extracted with chloroform. The chloroform layer is then purified by silica gel column chromatography, and the resulting oily product is treated as in Example 1-a to obtain 2.32 grams (yield 41% of N-(o-chlorocinnamyl)-isoindoline hydrochloride as crystals having a melting point of 170°-172° C. (decomposition).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:23]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[CH:17][CH:18]=1)[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)=[O:9])#[N:24]
Reactant: CCOC(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)c1ccc(C(C#N)C(=O)c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a solution of ethyl isonicotinate (12 g) and 4-(1,1-Dimethylethyl)phenylacetonitrile (9.1 g) in tert-butyl alcohol (36 mL), was added potassium tert-butoxide (7.3 g), and the mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain 2-cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.09 g, yield 35%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].[C:34](=[O:37])([O-])[O-].[K+].[K+].[ClH:40]>CN(C)C=O.C(OCC)(=O)C>[ClH:40].[ClH:40].[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:3][C:4]#[C:5][CH2:6][N:8]2[CH2:13][CH2:34][O:37][CH2:10][CH2:9]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc2ccccc2c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (200 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (95 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (177 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2-butynyl)-2-(2-naphthylmethyl)piperazine dihydrochloride (257 mg).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH3:9]>>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: N
Reactant: O=C(O)/C=C\C(=O)O
Product: O=C([O-])/C=C\C(=O)[O-]
Product: [NH4+]

Procedure:
combining maleic acid and ammonia in an aqueous medium to produce an aqueous solution of an ammonium maleate;
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[CH:17]=[CH:16]3)[CH2:5][CH2:4]1.CCN(CC)CC.[O:29]=[C:30]1[CH2:35][S:34][C:33]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[N:39][C:32]=2[NH:31]1.[BH4-].[Na+]>CO.C(Cl)Cl>[O:21]=[C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[C:11]([CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][CH:3]([NH:2][CH2:40][C:38]4[CH:37]=[CH:36][C:33]5[S:34][CH2:35][C:30](=[O:29])[NH:31][C:32]=5[N:39]=4)[CH2:4][CH2:5]3)[CH:12]=[CH:13][CH:14]=2)[O:19]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: NC1CCN(CCc2cccc3ccc(=O)oc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CSc2ccc(CNC3CCN(CCc4cccc5ccc(=O)oc45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 8-[2-(4-amino-1-piperidinyl)ethyl]-2H-chromen-2-one hydrochloride (41 mg, 0.15 mmol), Et3N (0.10 mL), in 10% methanol/CH2Cl2 (5 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (32 mg, 0.17 mmol). The solution was allowed to stir at RT for 16 h, then sodium borohydride (7 mg, 0.17 mmol) was added. The solution was stirred for an additional 30 min then was concentrated under reduced pressure. Flash chromatography on silica gel (90:9:1 CHCl3/MeOH/conc NH4OH) gave the title compound (34 mg, 51%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J=9.6 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.50-7.62 (m, 2H), 7.32 (m, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.47 (d, J=9.6 Hz, 1H), 4.17 (s, 2H), 3.57 (s, 2H), 3.36-3.04 (m, 5H), 3.00-2.84 (m, 2H), 2.62-2.38 (m, 2H), 2.33-2.10 (m, 2H), 1.87-1.62 (m, 2H); MS (ES) m/e 451.1 (M+H)+.
Reaction SMILES: CC[C@H]([C@H]([CH2:13][N:14](C)[CH3:15])C)C1C=CC=C(O)C=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25](=[O:28])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=1.[ClH:29].[CH3:30]NC.C=O>>[ClH:29].[CH3:13][N:14]([CH3:15])[CH2:27][CH:26]([CH3:30])[C:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:28]
Reactant: CNC
Reactant: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Reactant: CCC(=O)c1cccc(OC)c1
Agent: C=O
Agent: Cl
Product: COc1cccc(C(=O)C(C)CN(C)C)c1

Procedure:
WO2008012047 describes yet another method for the preparation of tapentadol, wherein 1-(3-methoxyphenyl)propan-1-one is reacted with dimethyl amine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride, which after reacting with sodium hydroxide is reacted with (2R,3R)—O,O′-dibenzoyl tartaric acid monohydrate to get (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one L-(−)-dibenzoyltartarate. The dibenzoyl tartrate salt is further reacted with diethyl amine to isolate keto compound (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one. The keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The hydrochloride salt of the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol on reaction with aqueous hydrochloric acid undergoes dehydration yielding the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, which after hydrogenation using homogeneous or heterogeneous catalyst results in the mixture of compound (2R,3R))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine having Z:E ratio of 5.5:1. The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methane sulphonic acid and treated with methionine to get the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I, which is isolated as hydrochloride salt of tapentadol hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1)[CH3:22]
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 74 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-ethoxybenzeneboronic acid according to the procedure described in example 8 gave 4-(2-ethoxyphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (504) (I; Ar=2-ethoxyphenyl) in a 74% yield; mp (THF/CH2Cl2/hexane) 190–193° C. (dec). 1H NMR [(CD3)2SO] δ 11.71 (br s, 1H), 10.91 (br s, 1H), 9.23 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.38 (td, J=7.8, 1.7 Hz, 1H), 7.33 (dd, J=7.5, 1.7 Hz, 1H), 7.07 (br d, J=6.7 Hz, 1H), 7.05 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (dd, J=7.3, 6.6 Hz, 1H), 3.97 (q, J=6.7 Hz, 2H), 1.11 (t, J=6.9 Hz, 3H). Found: C, 70.63; H, 4.74; N, 6.88. C22H16N2O4.1/4 THF requires C, 70.76; H, 4.65; N, 7.18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)C)=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CN([CH:22]=[O:23])C>C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:22][OH:23])=[CH:4][C:3]=1[Br:18]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(CCO)cc1Br

Procedure:
A solution of 4-aminophenyl ethanol (34 g, 0.25 mol) and NBS (35 g, 0.20 mol) in DMF (660 mL) was stirred at RT overnight. Then the mixture was diluted with ethyl acetate (2 L), washed with water (300 mL×4), dried over Na2SO4, concentrated in vacuo to give the crude product 2-(4-Amino-3-bromophenyl)ethanol. 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=1.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.70 (s, 1H), 4.44 (br, 1H), 3.76 (t, J=6.4 Hz, 2H), 2.71 (t, J=6.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH:25]=[CH2:26])[CH:3]=1.C(Cl)Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH2:25][CH3:26])[CH:3]=1
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C

Procedure:
A mixture of 4-(4-chloro-2-vinyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo-[3,4-e][1,4]thiazepine (0.100 g, 0.26 mmol, Preparation #18) and palladium hydroxide on carbon (0.073 g, 20 wt % on dry basis, ˜0.1 mmol), in methanol (5 mL) and DCM (2 mL) was treated with hydrogen (1 atm.), at rt, overnight. Then the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method b) to give 4-(4-chloro-2-ethyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine as an off white solid: LC-MS (Table 1, Method a) Rt=4.03 min; m/z 385 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.38 (3 H, t, J=7.5 Hz) 2.71 (1 H, ddd, J=15.1, 6.3, 2.7 Hz) 2.83 (1 H, ddd, J=15.1, 8.8, 2.8 Hz) 2.94 (1 H, dq, J=15.1, 7.5 Hz) 3.10 (1 H, dq, J=15.1, 7.5 Hz) 3.18-3.27 (1 H, m) 3.52-3.60 (1 H, m) 3.79 (1 H, br s) 3.84 (3 H, s) 6.78 (1 H, s) 6.99 (1 H, dd, J=8.4, 2.2 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 0.9 Hz) 7.13 (1 H, d, J=8.4 Hz) 7.20 (1 H, d, J=2.2 Hz) 7.59 (1 H, td, J=7.8, 1.7 Hz) 7.79 (1 H, dt, J=8.0, 0.9 Hz) 8.44 (1 H, ddd, J=4.8, 1.7, 0.9 Hz).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1.C(Br)C1C=CC=CC=1>[CH2:18]([O:16][C:15](=[O:17])[C@H:9]([CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: ClCc1ccccc1
Agent: BrCc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)OCc1ccccc1
Yield: 59.8 %

Procedure:
147 g N-BOC-glutamin (t-butyloxycarbonyl-glutamin), 77 g benzylchloride and 4 g benzylbromide were refluxed in 600 ml tetrahydrofuran for 2.5 hours in the presence of a 5% excess of diazabicycloundecene. After the removal of the solvent, the residue was taken up in water-ethylacetate and washed with citric acid, sodium bicarbonate and water. Evaporating of the solvent and recrystallization from ethylacetate-hexane gave 120 g white crystals. NMR (DMSO-d6) among others: 7.36 (s,5H), 5.12 (dxd,2H), 3.989 (m,1H), 2.15 (t,2H), 1.38 (s,9H).