Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([OH:20])[CH2:10][CH2:11][O:12][CH2:13]4.[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([OH:20])[CH2:10][CH2:11][O:12][CH2:13]3)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCOC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC[C@]23COCC[C@@]2(O)[C@H]1Cc1ccc(OC)cc13

Procedure:
A mixture of 3-methoxy-14β-hydroxy-6-oxamorphinan (X) (0.005 m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: COc1ccccc1-c1ccc(-c2nc(CCN3CCC[C@H]3C)c(C)o2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 67 mg (62%). MS (m/e) 377.2 (M+1)
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16]Br)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>C(Cl)Cl.CO.NC(N)=O>[C:19]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][CH2:16][CH:15]([OH:18])[C:13]2[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][CH:12]=2)=[CH:26][CH:25]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(Nc1nc(C(=O)CBr)cs1)c1ccccc1
Reactant: CCOC(=O)c1ccc(CCN)cc1
Agent: NC(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
9.6 g (0.03 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolved in 100 ml of methylene chloride and, while stirring at room temperature, added dropwise to a solution of 11.5 g (0.06 mol) of 2-(4-carboethoxyphenyl)ethylamine in 150 ml of methylene chloride. After 1.5 hours, the mixture is cooled to 5° C., diluted with 200 ml of methanol and, for the reduction of the resulting amino-ketone, 3 g of sodium borohydride are added in small portions at 0°-5° C. After 3 hours the solution is evaporated to dryness, ice/water is added, and hydrochloric acid is used to acidify. After 10 minutes the mixture is made alkaline with sodium bicarbonate solution and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using chloroform/methanol =9:1, with the addition of 2% ammonia-saturated ethanol, as eluant. The resulting product is induced to crystallise with petroleum ether.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]2[O:9][CH2:10][O:11][C:6]2=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C[O-].[Na+].C(O)(=O)C>CO.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([NH:2][CH3:1])[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]=1[OH:11]
Reactant: CNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CNc1cc(OC)c(O)cc1[N+](=O)[O-]

Procedure:
A solution of 0.1 mol (19.6 g) of 2-methylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 3, in 80 ml of a 30% strength solution of sodium methylate in methanol is brought for 15 minutes to the refluxing temperature of the methanol. The reaction medium is diluted with 500 ml of water. After the filtrate has been neutralized with acetic acid, the expected product precipitates.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH:89]([CH3:91])[CH3:90])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:49][C@@H:50]([CH:89]([CH3:90])[CH3:91])[C:51]([O:53][C@H:54]1[C@H:59]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH2:58][CH2:57][N:56]([C:65]2[CH:70]=[C:69]([C:71]#[N:72])[CH:68]=[C:67]([NH:73][C:74]3[N:79]=[C:78]([NH:80][CH2:81][CH3:82])[C:77]4=[N:83][CH:84]=[C:85]([C:86]#[N:87])[N:76]4[N:75]=3)[C:66]=2[Cl:88])[CH2:55]1)=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@@H](N)C(C)C)C3)c2Cl)nn2c(C#N)cnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of (S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid (30 mg, 0.087 mmol) in dry DCM (1 mL) was added TBTU (27.5 mg, 0.086 mmol) and TEA (0.030 mL, 0.214 mmol) under N2 atmosphere. The reaction mixture was stirred 0.5 h at the same temperature and (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-amino-3-methylbutanoate dihydrochloride (36.5 mg, 0.053 mmol) was added. The reaction stirred 1 h at room temperature; the LCMS showed complete conversion. The reaction mixture was diluted with DCM, washed with water, and dried over Na2SO4. The solvent was removed and the reaction mixture was taken-up in DCM and purified on a silica gel column: eluting with 10-80% acetone-hexane to afford (S)-(3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((S)-2,6-bis((tert-butoxycarbonyl)amino)hexanamido)-3-methylbutanoate.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([F:25])[C:3]=1[C:4]#[N:5].[NH2:26][NH2:27].CCN(C(C)C)C(C)C.C(O)C>O.CCOC(C)=O>[F:25][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:26][NH:27]2
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cc(F)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 68.6 %

Procedure:
A 2-mL microwave vial was charged with 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (75 mg, 0.217 mmol), hydrazine (0.027 mL, 0.869 mmol), Hunig's base (0.152 mL, 0.869 mmol) and ethanol (1 mL). The reaction mixture was heated at 150° C. for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool, then was poured into EtOAc (50 mL) and water (25 mL). The aqueous layer was extracted with two further portion of EtOAc (2×50 mL), and the combined organics dried over Na2SO4. The dried solution was filtered and concentrated, and the resulting residue was purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA) to afford the title compound (53.2 mg) as a yellow solid. LC-MS (ES) m/z=358 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.6 Hz, 3H), 2.83 (bs, 3H), 3.06-3.20 (m, 1H), 3.40-3.52 (m, 1H), 3.55-3.66 (m, 1H), 3.69-3.78 (m, 1H), 3.88-4.00 (m, 1H), 4.06-4.24 (m, 1H), 4.43-4.62 (m, 1H), 5.27 (bs, 2H), 6.45-6.71 (m, 2H), 7.26-7.49 (m, 1H), 7.76-7.96 (m, 1H), 11.71-12.13 (m, 1H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25]O)[CH2:20]2.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:20]2
Reactant: COc1cccc2c1CCC(CO)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1CCC(CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 24 h
Yield: 55.3 %

Procedure:
A solution of diethyl azodicarboxylate (871 mg) in tetrahydrofuran (4 ml) was added slowly to a stirred solution of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methanol (961 mg), phthalimide (736 mg), and triphenylphosphine (1.31 g) in tetrahydrofuran (10 ml) at room temperature and the resulting mixture was stirred at the same temperature for 24 hours. The reactIon mixture was evaporated in vacuo and the residue was chromatographed (toluene) over silica gel. The eluate was evaporated in vacuo and the residue was triturated with n-hexane to afford N-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]phthalimide (888 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>CCO.C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
A cooled (0° C.) suspension of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile (24.2 g, 100 mmol) in EtOH (150 ml) and THF (150 ml) was treated with SnCl22H2O (67.7 g, 300 mmol) and the mixture was stirred to ambient temperature over 12 h. The solvent was removed in vacuo and the residue treated with ice-cold aqueous 2 N NaOH solution (750 ml). The resulting slurry was stirred for 60 min then extracted with CH2Cl2 (2×400 ml). The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated to give a red solid. Crystallisation from toluene gave 5′-amino-2′-fluorobiphenyl-2-carbonitrile as a cream-coloured solid (16 g, 75%): δH (400 MHz, CDCl3 ) 3.65 (2H, br), 6.67-6.73 (2H, m), 7.00 (1H, t, J 9), 7.44-7.49 (2H, m), 7.64 (1H, td, J 9 and 2), 7.75 (1H, dd, J 8 and 2); m/z (ES+) 213 (100%, [MH]+).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:22]([CH2:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:11][C:10]([CH3:13])([CH3:12])[C@H:8]([NH:9][C:30](=[O:31])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)COc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38 mL, 2.73 mmol) and phenoxyacetyl chloride (0.14 mL, 1.01 mmol), stirred at 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate/chloroform to give the title compound (0.23 g, 80% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([Br:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.Cl.C(OCC)C>CN(C=O)C>[Br:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[O:16][CH2:19][O:20][CH3:21]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
40.00 g (140.2 mmol) of 2,4-di-tert-butyl-6-bromophenol and 400 ml of DMF are introduced into a one liter three-necked flask. The solution obtained is cooled to 5-10° C., 4.70 g of sodium hydride are added and the mixture is stirred at 10° C. for 30 minutes. 11.7 ml (154.0 mmol) of chloromethyl methyl ether are then added dropwise and the reaction mixture is stirred for one hour at room temperature. The reaction mixture is poured into a 1N HCl/ethyl ether mixture and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 46.00 g (130%) of the expected compound are collected in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1.[BH4-].[Na+]>C1COCC1.CO.Cl>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([OH:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzofuran-3(2H)-one (285 mg, 0.345 mmole) in THF/MeOH (9 mL/3 mL) was added NaBH4 (39.2 mg, 1.04 mmole) at 0° C. The resulting solution was stirred at 0° C. for 1 hr, diluted with 1N—HCl and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (260 mg, 91%) as a yellow gum.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 81.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (4.3 g) and 3-pyridinebutanamine (1.51 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual fashion. The crude product was crystallized from ethyl acetate-hexane to provide 3.6 g of (E)-5,5-bis(4-methoxyphenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 76°-77° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1>[Pd].CO>[CH3:29][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCCc2ccccc2)CC1
Reaction time: 16 h
Yield: 15 %

Procedure:
Palladium-on-charcoal (5%, 22 mg) was added to a solution of 2-[4-dimethylamino-4-(3-fluorophenyl)-cyclohexylidene]-N-(3-phenylpropyl)-acetamide (440 mg, 1.1 mmol) in abs. methanol (40 ml). The reaction mixture was hydrogenated at RT under a pressure of 3 bar for 16 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue by chromatography on silica gel G [(80 g; EA/MeOH (2:1)], the less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide was isolated as a colourless oil in a yield of 15% (64.3 mg) and the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-(3-phenylpropyl)acetamide was isolated as a colourless solid with an m.p. of 119-122° C. in a yield of 72% (314 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:7]=1.[BH4-].[Na+]>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCCC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Yield: 100.2 %

Procedure:
1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (140 mg, 0.49 mmol) was dissolved in 5 mL methanol. Sodium borohydride (18.7 mg, 0.494 mmol) was added. The reaction mixture was concentrated and the residue partitioned between water and ethyl acetate. The organic layer was concentrated to give 1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-ol (140 mg). 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.34-8.40 (m, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.82-7.90 (m, 2H), 4.75-4.82 (m, 1H), 1.64-1.89 (m, 2H), 1.27-1.53 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A 500 mL round-bottom flask was charged with 4-bromo-2-fluorobenzaldehyde (12.0 g, 59.1 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol, 1.00 equiv), triethylamine (8.10 g, 80.0 mmol, 1.49 equiv) and dichloroethane (100 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (34.2 g, 161 mmol, 3.01 equiv) was added. The resulting solution was stirred 5 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 16.0 g (80% yield) of tert-butyl 4-[(4-bromo-2-fluorophenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 373 [M+H]+.
Reaction SMILES: [CH3:1][S:2][S:3]([CH3:6])(=O)=O.[F:7][C:8]([F:19])([F:18])[CH:9]([C:11]1[CH:16]=[CH:15]C(S)=[CH:13][CH:12]=1)[OH:10]>CCO.C1COCC1>[F:7][C:8]([F:18])([F:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:1]([S:2][S:3][CH3:6])=[CH:13][CH:12]=1)[OH:10]
Reactant: CSS(C)(=O)=O
Reactant: OC(c1ccc(S)cc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CSSc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
Methanethiosulfonic acid S-methyl ester (0.02 ml, 0.22 mmol) was dissolved in an EtOH (0.46 mL) and saturated NaCO3/H2O (pH 8) solution (0.8 mL) under argon at 0° C. A solution of 2,2,2-trifluoro-1-(4-mercapto-phenyl)-ethanol (5) (22 mg, 0.11 mmol) dissolved in THF (1.5 mL) under argon was added dropwise. After 10 minutes, the reaction temperature was raised to room temperature. After 36 hours, the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL). The combined organic phases were dried over Na2SO4 and under reduced pressure. Flash chromatography on silica gel using 0-30% acetone/hexane gave Compound 15 as a yellow oil (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 4H), 5.02 (q, J=6.7 Hz, 1H), 2.45 (s, 3H); 19F NMR (376 Hz, CDCl3) δ −78.79 (d); 13C NMR (100 MHz, CH3OD): δ 137.6, 134.2, 128.8, 126.4, 124.6 (q, JCF=281.7 Hz), 71 (q, JCF=31.5 Hz), 21.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([N:7]([CH2:19][C:20](O)=[O:21])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][NH2:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][NH:6][C:20](=[O:21])[CH2:19][N:7]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:23]
Reactant: COC(=O)C(CN)N(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CNC(=O)CN1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-2-[carboxymethyl-(4-methoxybenzenesulfonyl)-amino]-propionic acid methyl ester trfluoracetic acid salt (2.11 grams, 6.1 mmol) in methylene chloride (5 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.76 grams, 9.2 mmol) and triethyamine (3.4 ml, 24.4 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and washed with 1N hydrochlori acid. The organic layer is dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with ethyl acetate) to provide 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid methyl ester.