Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11](Cl)=[O:12])#[N:3]>O1CCCC1.O>[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11]([NH2:1])=[O:12])#[N:3]
Reactant: N
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a stirred, ice-cold solution of 10 mL (0.15 mole) of concentrated aqueous ammonia in 15 mL of tetrahydrofuran was added dropwise a solution of 0.35 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 15 mL of tetrahydrofuran. Upon completion of the addition, the cooling bath was removed. The reaction vessel was closed by placing a rubber balloon over the open inlet of the reaction vessel. The reaction mixture was then allowed to warm to ambient temperature where it was stirred for one hour. After this time, the reaction mixture was concentrated at 45° C. under reduced pressure to a residual solid. The solid was triturated with petroleum ether and filtered, yielding a solid that did not completely melt at 212° C. The filtrate was concentrated in an air current, yielding a tan-yellow solid. Both solids were stirred in water separately. Each of the solids was then collected by filtration. The tan-yellow solid was triturated with two drops of isopropyl alcohol and petroleum ether. The suspension was cooled in a dry ice bath, and the solid was collected by filtration. The two solids were combined and dried, yielding 0.18 gram of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]- acrylamide, m.p. 208°-210° C., dec. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:8]([OH:24])=[C:9]([C:21](=[O:23])[CH3:22])[CH:10]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]([C:9]1[C:8]2[O:24][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:23])[CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.0 mL (258 mmol) chloroacetyl chloride are added dropwise to 60.0 g (233 mmol) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) potassium carbonate while being cooled with the ice bath. Then the mixture is stirred overnight at ambient temperature and then for 6 hours at reflux temperature. The hot reaction mixture is filtered, then evaporated down to approx. 400 mL and combined with ice water. The precipitate obtained is suction filtered, dried and purified by chromatography on a short silica gel column (dichloromethane:methanol=99:1). The fractions containing the product are evaporated down, suspended in isopropanol/diisopropylether, suction filtered and washed with diisopropylether. Yield: 34.6 g (50%); mass spectroscopy [M+H]+=298.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[CH3:18][O:19][C:20]([C:22]1(OC)[CH2:26][CH2:25][CH:24](OC)O1)=[O:21]>>[CH3:18][O:19][C:20]([C:22]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[CH:24]=[CH:25][CH:26]=1)=[O:21]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F

Procedure:
51 mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 51 mmol of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]2[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][N:13]([C:28]3[C:29]4[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=4[N:31]=[CH:32][N:33]=3)[C:10]2=[CH:11][CH:12]=1>C1COCC1.CCOC(C)=O.[Zn+2].[Br-].[Br-].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>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]4)[CH2:14][N:13]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[C:10]3=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C5CC5)ccc43)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a stirred suspension of ZnBr2 (41 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise a 0.5 M solution of cyclopropylmagnesium bromide in THF (0.36 mL, 0.18 mmol) at about −78° C. under nitrogen. After being stirred at about −78° C. for about 30 min, the resulting solution was allowed to warm to about 0° C. A solution of (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (38 mg, 0.076 mmol) and Pd(PPh3)4 (4.4 mg, 0.0038 mmol) in THF (0.3 mL) was added. The resulting mixture was heated to about 60° C. overnight. After cooling, the mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by reverse phase preparative HPLC to give (R)-tert-butyl 5-cyclopropyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 57%). LCMS (APCI+) m/z 461 [M+H]+; Rt=3.24 min.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(=[O:10])[C:7]([CH3:9])=O>>[NH2:5][C@H:7]([C:6]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:9]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Moreover, by following the procedure described in Example 4 but using ammonium acetate to make the acetylimine of N-pyruvyl-L-proline, a 65% diastereomeric excess of L-alanyl-L-proline was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([Si]([C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])(CC)CC)C>CO.O>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[C:17]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28])#[CH:14]
Reactant: CC[Si](C#Cc1cccc(C(F)(F)F)c1CC(=O)OC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cccc(C(F)(F)F)c1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
K2CO3 (0.210 g, 1.52 mmol) was added to a solution of methyl 2-(2-((triethylsilyl)ethynyl)-6-(trifluoromethyl)phenyl)acetate (A92) (0.175 g, 0.491 mmol) in MeOH (1 mL) and the mixture stirred for 10 minutes at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue dissolved in MeOH (1 mL). K2CO3 (0.204 g, 1.48 mmol) was added and the mixture stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3×20 mL) then the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) to which K2CO3 (0.230 g, 1.66 mmol) was added and the resulting mixture stirred at room temperature for 30 minutes. Water (20 mL) was added and the mixture extracted with DCM (3×20 mL). The combined organic extracts were concentrated under reduced pressure to give the title compound A93 (0.113 g, 95%); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 4.08 (m, 2H), 3.70 (s, 3H), 3.35 (s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:22]>CN(C=O)C>[C:1]([O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][OH:22])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(COC(=O)c2ccccc2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(CO)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride, followed by stirring at room temperature overnight. After evaporating trifluoroacetic anhydride under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 3.675 g of [6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:25]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([I:25])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cn[nH]c3c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(I)n[nH]c3c2)CC1
Reaction time: 16 h
Yield: 38 %

Procedure:
A stirred solution of 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-1H-indazole (7.20 g, 23.8 mmol) in N,N-dimethylformamide at 0° C. is treated with powdered potassium hydroxide (5.40 g, 95.4 mmol) followed by the dropwise addition of a solution of iodine (10.9 g, 42.9 mmol) in N,N-dimethylformamide, stirred at ambient temperatures for 16 h, diluted with ethyl acetate and quenched with 10% aqueous sodium metabisulfite solution. The phases are separated. The aqueous phase is extracted with ethyl acetate. The extracts are combined with the organic phase, washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude material is purified by flash chromatography (silica gel, 30:70 ethyl acetate/hexanes) to afford the title compound as a yellow solid, 3.4 g (38% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([N+:17]([O-])=O)[CH:4]=[N:3]1.[NH4+].[Cl-]>CO.O.[Zn]>[CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([NH2:17])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCNC(C(F)(F)F)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Cn1ncc(N)c1N1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of (±)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-(trifluoromethyl)piperazine (420 mg, 1.5 mmol) in MeOH (20 mL) and H2O (5 mL) was added zinc (590 mg, 4 mmol) and NH4Cl (805 mg, 10 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE/EtOAc (10/1˜1/10) as eluting solvents to afford (±)-1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-amine (340 mg, 90%) as red solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 6.84 (s, 1H), 3.38-3.52 (m, 5H), 3.13-3.17 (m, 2H), 2.94-3.00 (m, 2H), 2.50-2.78 (s, 3H), 1.98 (m, 1H); MS (ESI) m/z: 250 (M+1+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:15][C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: Clc1cc(Cl)nc(NC2CCCC2)n1
Yield: 35.2 %

Procedure:
The reaction of 2,4,6-trichloropyrimidine with cyclopentylamine carried out as described in Example 35 gives both compounds. The less polar 2-cyclopentylamino-4,6-dichloropyrimidine is obtained in a yield of 35.2%, m.p.: 48°-52° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][NH:5][C:6]=1[NH2:7].CO[CH:16](OC)[CH2:17][CH:18](OC)OC.O.[NH4+].[OH-]>C(O)(=O)C>[Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][N:5]2[CH:18]=[CH:17][CH:16]=[N:7][C:6]=12
Reactant: Nc1[nH]nc(-c2ccccc2)c1Br
Reactant: COC(CC(OC)OC)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1c(-c2ccccc2)nn2cccnc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 4-bromo-3-phenyl-1H-pyrazole-5-amine (5.0 g, 0.02 mol) in acetic acid (50 mL) is added 1,1,3,3-tetramethoxypropane (4.14 g, 0.025 mol). The mixture is stirred at 110° C. for 1 h. The reaction mixture is then poured into water, basified with NH4OH and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in dichloromethane and ethyl acetate (1:0 to 95:5) as eluent and 4.2 g (75%) of 3-bromo-2-phenylpyrazolo[1,5-a]pyrimidine are obtained as a beige solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: CCN(CC)Cc1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O
Yield: 95 %

Procedure:
Following the procedure of Example 9(4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: 95.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:29](=[O:31])[CH3:30])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(NC(C)=O)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
Combine 3-(4-aminophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in CH2Cl2 (5 mL) and stir. Add triethylamine (1.5 eq) and acetyl chloride (1.0 eq) at room temperature. Stir the mixture overnight. Add a saturated solution of NH4Cl and extract with CH2Cl2 (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purification by chromatography (hexane: ethyl acetate 4:1) provides the title compound (0.125 g, yield 90%). MS (ES+, m/e): 361 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[OH:18][C:19]1[C:20]([C:27]([NH:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:16][CH:15]=2)=[O:28])=[N:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccnc(C(=O)Nc2ccc(OCc3ccccc3)cc2)c1O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
4-Benzyloxyaniline hydrochloride (0.21 g, 0.87 mmol), 0.15 g (0.73 mmol) of 3-hydroxy-4-methoxypicolinic acid hydrochloride, 0.15 g (1.10 mmol) of 1-hydroxybenzotriazole, and 0.16 g (1.10 mmol) of triethylamine were mixed into chloroform to prepare a suspension (2 ml). A chloroform solution (2 ml) of WSCI.HCl (0.21 g, 1.10 mmol) and 0.11 g (1.10 mmol) of triethylamine were added dropwise at −20° C. to this suspension, and a reaction was then allowed to proceed at room temperature overnight. The reaction mixture was concentrated under the reduced pressure. The concentrate was redissolved in chloroform. The solution was washed with saturated brine, and was then dried over anhydrous sodium sulfate. The dried solution was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give 0.15 g (yield 59%) of title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH3:41])[CH:33]=1)=[O:31]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH3:41])[CH:33]=3)=[O:31])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cn1cc(C(=O)CCCCCCBr)c2ccccc21
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2cn(C)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 7-bromo-1-(1-methyl-1 H-indol-3-yl)-1-heptanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(7-(1-methyl-1 H-indol-3-yl)-7-oxoheptyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:12](O)[CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:15][CH2:14][CH2:13][CH2:12][O:6]2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Br)cc(C2OCCCO2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 3-bromo-5-methoxybenzaldehyde (3.93 g, 18.2 mmol), propane-1,3-diol (1.6 mL, 21.8 mmol) and p-toluenesulfonic acid monohydrate (0.104 g, 0.54 mmol) in anhydrous toluene (100 mL) was brought to reflux for 18 h under nitrogen. During this time water was removed using a Dean-Stark apparatus. After this time the reaction was cooled to rt, washed with 5% aqueous Na2CO3 solution (50 mL) and dried over anhydrous Na2SO4. The reaction was concentrated under reduced pressure to give 2-(3-bromo-5-methoxyphenyl)-1,3-dioxane (4.80 g, 96%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: CN1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1F
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CN1CCN(C(=N)Nc2ccccc2-c2ccccc2F)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.1 g) and N-methylpiperazine (1.5 g) in ethanol (25 ml) was heated at 90°-95° C. for 3 hours to yield the free base which was reacted with fumaric acid (1.78 g) in methanol (70 ml) to give N-(2'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine difumarate (m.p. 201°-202° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58]>O1CCCC1>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:58][CH2:57][CH2:56][CH:55]([CH3:59])[CH3:54])=[O:10]
Reactant: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.24 g, 0.73 mmol) in dry tetrahydrofuran (10 ml) are added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.30 g, 0.80 mmol) and triethylamine (0.38 ml, 2.2 mmol) at RT. The reaction mixture is stirred for 5 min at RT followed by the addition of 3-methyl-butyl-amine (0.1 ml, 0.88 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with saturated sodium hydrogen carbonate solution (20 ml) before extraction with EtOAc (3×30 ml). The organic layer is washed with saturated ammonium chloride solution (30 ml), water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-benzamide (example 1) (0.16 g, 0.41 mmol, 56%). [M+H]+ 396.1.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(CCCF)N=C(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)(CCCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
16.73 g (59.68 mmol) of rac-2-[(diphenylmethylene)amino]-5-fluoropentanonitrile from Example 68A were initially charged in 394 ml of abs. THF, and 24.11 ml (60.27 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 34.93 g (238.70 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 4.5 h. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 18.94 g of the target compound were obtained (95% of theory, 88% purity).