Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])C.[CH:14]([NH2:17])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+]>C(O)C>[CH:14]([N:17]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:6]([OH:13])=[O:7])=[CH:4]1)([CH3:16])[CH3:15]
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Reactant: CC(C)N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)c(C(=O)O)cn1C(C)C

Procedure:
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 3a, 10.00 g, 38.6 mmol based on 70% purity), isopropylamine (5.00 mL, 58.4 mmol) and sodium tert-butoxide (5.50 g, 57.2 mmol) in ethanol (20 mL) is heated for 18 h at 90° C. The reaction mixture is evaporated under reduced pressure, treated with water and extracted with dichloromethane. The aqueous layer is acidified with 4 N aqueous HCl and extracted with dichloromethane. The combined organic layer is washed with water, dried over Na2SO4 and evaporated under reduced pressure. Yield: 7.16 g; ESI mass spectrum: [M+H]+=196; Retention time HPLC: 0.71 min (Z002_006).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15]1
Reactant: CS(=O)(=O)OC1CCN(C2CC2)C1
Reactant: Oc1ccccc1Br
Product: Brc1ccccc1OC1CCN(C2CC2)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-cyclopropylpyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[O:4][C:5]1[C:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([OH:15])[CH2:10][CH2:9][CH2:8]2>[O-2].[O-2].[Mn+4].O1CCCC1>[OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[O:4][C:5]1[C:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Reaction time: 4 h
Yield: 87 %

Procedure:
A mixture of 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenol (0.756 g, 2.22 mmol), tetrahydrofuran (5 mL), and manganese dioxide (4.6 g) was stirred for 4 h. The mixture was filtered through Celite and the filter cake was washed thoroughly with dichloromethane. The combined filtrates were concentrated to give 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone as a pale yellow solid, 0.656 g, 87% yield. NMR spectrum was consistent with structure. Calcd. for C22H26O3: Theory: C, 78.08; H, 7.74. Found: C, 77.90; H, 7.75. 4. 2-Methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethanesulfonate
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH2:32]([O:34][C:35]([C:37]1[N:38]([CH3:48])[C:39]2[C:44]([C:45]=1[Cl:46])=[CH:43][C:42]([NH2:47])=[CH:41][CH:40]=2)=[O:36])[CH3:33]>C(Cl)Cl.CN(C=O)C>[CH2:32]([O:34][C:35]([C:37]1[N:38]([CH3:48])[C:39]2[C:44]([C:45]=1[Cl:46])=[CH:43][C:42]([NH:47][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[CH:41][CH:40]=2)=[O:36])[CH3:33]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1c(Cl)c2cc(N)ccc2n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4′-Trifluoromethyl-2-biphenylcarboxylic acid was converted to the corresponding acid chloride by treatment with oxalyl chloride in methylene chloride in the presence of catalytic amount of DMF. To a solution of the acid chloride (10.8 g, 38 mmol) and pyridine (3.27 mL, 40 mmol) in methylene chloride (200 mL) was added the product of step (c) (10.1 g, 40 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted to 600 mL with CH2Cl2, washed with 0.1 N HCl solution (2×500 mL) and with brine (500 mL), and then dried (MgSO4). The solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from EtOAc/isooctane to afford 13.8 g of the title compound.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8]1.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8]1
Reactant: CC1CC(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 69.7 %

Procedure:
As presented in the following reaction formula, a solution of potassium nitrate (KNO2; 6.2 g, 0.06 mol) in sulfuric acid (30 mL) was added dropwise at 0° C. to a mixture of 3-methyl-2,3-dihydro-1H-inden-1-one (9.0 g, 0.06 mol) in sulfuric acid ic (H2SO4; 40 mL). Then, the mixture was stirred at 0° C. until the completion of reaction. The mixture obtained after the reaction was added to ice water and filtered. The cake was washed with water and purified by silica gel (100 g) column chromatography (product of Merck Co., Ltd.) using an eluent of pentane (PE):ethyl acetate (10:1 (by volume)) to give 3-methyl-6-nitro-2,3-dihydro-1-H-inden-1-one (8 g, yield: 69%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C.C(OCC)(=O)C>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:20][CH2:19][CH2:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Method A: Palladium on carbon (60 mg of 10%) was added to a solution of Example 1 (60 mg, 0.16 mmol) in 60 mL of ethanol and 10 mL of ethyl acetate. The reaction vessel was flushed with H2. The resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 4 hours. The mixture was filtered and concentrated to provide the desired product (60 mg, 100% yield) as a colorless solid. ESI-MS m/z 373 (MH+); 1H NMR (500 MHz, CDCl3) δ 1.22 (m, 1H), 1.39 (m, 2H), 1.65 (m, J=12.51 Hz, 1H), 1.76 (d, J=8.85 Hz, 2H), 1.91 (d, J=11.90 Hz, 1H), 1.91 (d, J=11.90 Hz, 1H), 2.06 (m, 3H), 2.38 (m, 1H), 2.56 (m, 1H), 2.68 (dd, J=13.43, 6.71 Hz, 1H), 2.91 (m, 1H), 3.70 (m, 1H), 3.97 (m, 3H), 4.43 (dd, J=14.34, 6.71 Hz, 1H), 7.35 (m, 4H), 7.73 (dd, J=8.54, 1.53 Hz, 1H), 7.87 (d, J=8.54 Hz, 1H), 8.08 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[CH2:12]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(=O)C1
Agent: Cl
Product: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(S)-1-(2-Amino-3-phenyl-propionyl)-pyrrolidin-3-one hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first, then base) and the product purified by chromatography on silica gel eluted with 40 and 50% ethyl acetate in hexanes, followed by trituration of the resulting foam with ether. Yield 112 mg, 45%; HPLC (60/40) 5.13 minutes (>99%); PBMS 410/412 (MH+, 100%);
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[C:13]([F:15])[C:12](F)=[C:11]([F:17])[CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:15][C:13]1[CH:14]=[C:9](/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:10]=[C:11]([F:17])[C:12]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(F)c(F)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccccc2)c(F)c1
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of (E)-ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate (Intermediate 41.1, 6.0 g, 24.56 mmol) in dry DMF (25 mL) under N2 was added phenol (2.774 g, 29.5 mmol) and K2CO3 (10.2 g, 73.68 mmol). The resulting solution was brought to 120° C. and stirred for 3 hours at which point TLC indicated complete conversion. The solvent was removed by rotary evaporation and the resulting residue brought up in EtOAc (200 mL) and washed with water (2×200 mL), 1N NaOH (2×200 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and concentrated to yield 6.94 g (89%) of the title compound as tan crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][CH:3]([CH2:2][NH:14][CH2:15][CH2:16][CH2:17][OH:18])[O:4]2)=[CH:9][CH:8]=1
Reactant: Oc1ccc2c(c1)OC(CBr)CC2
Reactant: NCCCO
Solvent: O
Product: OCCCNCC1CCc2ccc(O)cc2O1
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 2-bromomethyl-7-hydroxychroman (4.57 g, 18.8 mmol) and 3-amino-1-propanol (18.3 mL, 240 mmol) is heated at 100° C. for 2 hr, cooled, diluted with water and extracted with CH2Cl2. The combined extracts are concentrated in vacuo to give a residue. The residue is purified by column chromatography (silica gel/5% methanol in CH2Cl2 as eluent) to give the title product as a clear oil, 3.27 g (73% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[Br:7][C:5]1[N:6]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
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: COCCOC
Product: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(Br)c1Br
Temperature: 110 °C
Yield: 86.5 %

Procedure:
A microwave vial was charged with 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (881 mg, 2.0 mmol, Example 2, Step 2), 4-fluorophenyl boronic acid (308 mg, 2.2 mmol), aqueous Na2CO3 solution (6 ml, 2.0 M, 12.0 mmol) and DME (12 ml). The mixture was sparged with argon for 15 min, followed by addition of Pd(PPh3)4 (120 mg, 0.1 mmol). The reaction vial was sealed and heated at 110° C. for 20 minutes in a microwave reactor; the reaction was deemed complete by LCMS. The reaction mixture was partitioned between saturated Na2CO3 solution and EtOAc (10 ml/30 ml), the organic layer was separated, washed with brine (10 ml), dried (Na2SO4), and concentrated. The resulting residue was purified by flash column chromatography (SiO2; 100:0-80:20 hexanes-EtOAc) to furnish 4,5-dibromo-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (780 mg, 1.73 mmol, 87%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.70 (m, 2H), 7.37 (app t, J=9.0 Hz, 2H), 5.33 (s, 2H), 3.52 (t, J=8.2 Hz, 2H), 0.83 (t, J=8.2 Hz, 2H), −0.06 (s, 9H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH:15]1[C:19]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])=[N:18][N:17]=[N:16]1>CC(O)C>[NH:18]1[C:19]([C:20]2[CH:21]=[C:22]([NH:23][C:2]3[O:3][C:4]([C:7]4[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)=[CH:5][N:6]=3)[CH:24]=[CH:25][CH:26]=2)=[N:15][N:16]=[N:17]1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(-c4nnn[nH]4)c3)o2)cc1
Temperature: 80 °C
Yield: 100.6 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.216 g, 1.05 mmol) and commercially available 3-(1H-tetrazol-5-yl)aniline 35 (0.17 g, 1.05 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was further purified by dissolving into DMSO and re-precipitated with addition of water. Resulting solid was filtered, washed with water, methanol and dried under high vacuum to yield 4-(2-((3-(1H-tetrazol-5-yl)phenyl)amino)oxazol-5-yl)benzonitrile 36 as a white solid (0.348 g, 100%). MS (ES) m/z 330 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]#[N:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:18]#[N:19]
Reactant: ClCCN1CCCCC1
Reactant: N#CCc1ccccc1Cl
Product: N#CC(CCN1CCCCC1)c1ccccc1Cl

Procedure:
The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives having the following formula: ##STR1## which comprises reacting 1-(2-chloroethyl)piperidine with 2-chlorobenzeneacetonitrile to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; alkylating the piperidenebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)piperidine-1-butanenitrile; hydrolyzing the resulting alkylated piperidinebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)piperidine-1-butanenitrile; reacting the resulting piperidinebutanenitrile with isopropylamine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)imino]ethyl]piperidine-1-butanenitrile; reducing the resulting imine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-piperidine-1-butanenitrile; acetylating the resulting amine to form (±)-N-[3-(2-chlorophenyl)-3-cyano-5-(1-piperidinyl)pentyl]-N-(1-methylethyl)acetamide; hydrolyzing the resulting acetylated amino substituted piperidine butanenitrile to form (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide; and isolating the resulting piperidinebutanamide.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:5][CH:6]=1.BrC1C(C2C=CN=CC=2)=C(C2C=CC(F)=CC=2)NN=1.[CH2:39]1[C@@H:47]2[N:42]([CH2:43][CH2:44][C:45](=O)[CH2:46]2)[CH2:41][CH2:40]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][CH:6]=[C:2]([C:45]3[CH2:46][C@H:47]4[N:42]([CH2:41][CH2:40][CH2:39]4)[CH2:43][CH:44]=3)[C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2scc(Br)c2-c2ccncc2)cc1
Reactant: O=C1CCN2CCC[C@H]2C1
Agent: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Product: Fc1ccc(-c2scc(C3=CCN4CCC[C@H]4C3)c2-c2ccncc2)cc1
Yield: 23 %

Procedure:
Following a procedure similar to that described in Example 2-2), but using 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene prepared as described in 5) instead of 3-bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole, and using (S)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one instead of (±)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one, the resulting product was subjected to a dehydration reaction as described in Example 3 and then treated by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=10:10:1), to give the title compound (Rf=0.50, 263 mg) as a brown amorphous solid (yield 23%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:21])[CH2:16][C:17]([O:19]C)=O)[CH:11]=[CH:12][C:13]=1[Cl:14].[OH-].[Na+].C(N(CC)CC)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC.O>[Si:31]([O:19][CH2:17][CH2:16][C:15]([C:10]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1)=[CH2:21])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CC(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
11.76 g (0.28 mole) of lithium aluminum hydride were suspended in 500 ml of anhydrous tetrahydrofuran, and a solution of 69.06 g (0.28 mole) of methyl 3-(3,4-dichlorophenyl)-3-butenoate [prepared as described in step (a) above] in 500 ml of anhydrous tetrahydrofuran was slowly added dropwise under a nitrogen atmosphere at 0° C. over a period of 15 minutes. The reaction mixture was then stirred at the same temperature for 30 minutes, after which 500 ml of water and 500 ml of a 10% w/v aqueous solution of sodium hydroxide were slowly added. The mixture was then stirred at room temperature for 1 hour. It was then filtered through a Celite (trade mark) filter aid, and the filtrate was extracted three times, each time with 500 ml of ethyl acetate. The combined organic extracts were then dried over anhydrous magnesium sulfate. The solvent was removed from the extract by distillation under reduced pressure, and the resulting residue was dried under reduced pressure. The residue was then dissolved in 250 ml of anhydrous dimethylformamide, and then 47.12 ml (0.34 mole) of triethylamine, 6.88 g (0.06 mole) of 4-dimethylaminopyridine and 50.96 g (0.34 mole) of t-butyldimethylsilyl chloride were added, in that order, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling, for 2 hours. At the end of this time, 1 liter of ethyl acetate was added to the reaction mixture, and the mixture was washed, in turn, with ice-cooled 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 50:1 to 20:1 by volume as the eluent, to obtain 43.52 g (yield 47%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:25][C:26]([OH:28])=[O:27])=[CH:13][CH:14]=[C:15]([CH2:23][NH2:24])[C:16]=1[N:17]2[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:13][CH:14]=[C:15]([CH2:23][NH2:24])[C:16]=1[N:17]2[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1c2cccc(C(=O)OC(C)(C)C)c2Sc2c(CC(=O)O)ccc(CN)c21
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2cccc(C(=O)OC(C)(C)C)c2Sc2c(CC(=O)OCc3ccccc3)ccc(CN)c21
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
20 mg of N,N-dimethylaminopyridine and a solution of 455 mg (2.2 mmol) of N,N-dicyclohexylcarbodiimide in 5 ml of methylene chloride were added while cooling with ice to a solution of 801 mg (2.0 mmol) of (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetic acid and 324.5 mg (3.0 mmol) of benzyl alcohol in methylene chloride. The reaction mixture was stirred at 0° for 15 minutes, brought slowly to room temperature, stirred for 2 hours and then poured into ice and saturated sodium hydrogen carbonate solution, whereupon the mixture was extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 100 g of silica gel with ethyl acetate/hexane (3:2), whereupon 730 mg (74.4%) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetate were obtained as an amorphous solid. MS: 490 (M+ 78), 434(100), 416(22), 390(20), 91(60).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22](O)=[O:23])[CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CO>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:22]([CH:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[N:6]=2)[CH2:17]1)=[O:23]
Reactant: CNc1nc(N2CCN(C)CC2)nc(N2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(N2CCN(C)CC2)nc(N2CCCC(C(=O)NCc3ccccc3C(F)(F)F)C2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-3-piperidinecarboxylic acid (0.18 g, 0.55 mmol, 1.0 equiv), [(2-trifluoromethyl-phenyl)methyl]amine (0.12 g, 0.68 mmol, 1.25 equiv), and dimethylaminopyridine (DMAP, 14 mg, 0.11 mmol, 0.2 equiv) in CH2Cl2 and DMF was cooled to ˜0° C. using an ice bath. Next EDCI (0.16 g, 0.82 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 2 hours. The reaction was monitored by HPLC. The solution was then diluted with CH2Cl2 and washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, and concentrated to provide the crude product. The crude product was dissolved in methanol and purified by HPLC to afford 73 mg of the title compound. MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH3:6][C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[ClH:18].O>ClCCl>[F:15][C:14]1[CH:13]=[C:12]([F:16])[C:11]([F:17])=[CH:10][C:9]=1[C:7](=[O:8])[CH2:6][Cl:18]
Reactant: CC(=O)c1cc(F)c(F)cc1F
Reactant: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: O=C(CCl)c1cc(F)c(F)cc1F

Procedure:
40.8 g (0.3 mole) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mole) of 2,4,5-trifluoroacetophenone (obtained according to Example 6), dissolved in 400 ml of dichloromethane, and the mixture was stirred until the end of the evolution of hydrogen chloride (about 2 hours). 600 ml of water were then added to the reaction mixture, the organic phase was separated off, and this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5- trifluoro-phenacyl chloride were obtained as an oily residue, which corresponds to 84.5 % of theory. The characterization of the product carried out as in Examples 9 to 15 gave a δ value of 5.29 ppm.