Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:1][NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(CNc2cnccn2)CC1
Reaction time: 1 h

Procedure:
Benzyl 4-formyl-1-piperidinecarboxylate (P. E. Maligres, Tetrahedron, 53(32):10983–10992(1997)) (100 mg, 0.40 mmol) and aminopyrazine (46 mg, 0.48 mmol) were dissolved in toluene under N2 and was heated to reflux under Dean Stark conditions for 18 h. The volatiles were removed in vacuo and the residue taken up in ethanol and treated with solid NaBH4 (76 mg, 2.00 mmol) in small portions. The reaction aged at 20° C. for 1 h then was quenched with 2N HCl. The reaction was basified with 1M NaOH and was extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:18]=3)[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.C[NH:32][CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.[CH:40](N(CC)C(C)C)(C)C>C(O)CCC>[CH3:30][C:10]1[CH:11]=[CH:12][C:13]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:32][CH2:33][CH2:34][CH:35]2[CH2:39][CH2:38][CH2:37][N:36]2[CH3:40])[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCC1CCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1Nc1ccnc(NCCC2CCCN2C)n1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(3-morpholinobenzamido)anilino]pyrimidine (0.64 g), 2-(N-methylpyrrolidin-2-ylethylamine (0.44 ml), N,N-di-isopropylethylamine (0.52 ml) and n-butanol (7 ml) was stirred and heated to 100° C. for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound as a solid (0.33 g); NMR Spectrum: (DMSOd6) 1.44 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.15 (s, 3H), 2.31 (m, 4H), 3.04 (m, 2H), 3.17 (m, 5H), 3.74 (m, 4H), 5.88 (d, 1H), 6.5 (m, 1H), 7.13 (m, 2H), 7.34 (m, 2H), 7.44 (m, 2H), 7.77 (d, 1H), 7.9 (m, 1H), 8.37 (s, 1H), 10.04 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=2[CH:31]=1.O.CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[N:18]/[C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2ccc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 4-[(4-chlorophenyl)ethynyl]benzaldehyde (1.31 g, 5.43 mmol) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.00 g, 5.18 mmol) in toluene (20 ml) was heated at reflux for 18 h with azeotropic removal of water. Then the reaction mixture was cooled to rt and MeOH (20 ml) was added. The precipitate was filtered off, washed with MeOH and dried under reduced pressure to give 1.95 g of the titled compound as a yellow powder (91%). 1H NMR (CDCl3, 300 MHz) δ 8.42 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H, 7.65 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 6.91 (dd, J=8.3, 1.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 1.77 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:3]1=[O:21].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]1=[O:21]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a flask were placed 25.88 g (0.086 mole) of 1 -methyl-3-(4-methoxy-phenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 200 mL of methylene chloride. To this flask was added dropwise 258 mL (0.258 mole) of a 1 molar solution of boron tribromide in methylene chloride. Upon completion of addition, this reaction mixture was allowed to stir at ambient temperature for approximately 64 hours after which it was poured over ice. This mixture was filtered to remove insoluble material, and the aqueous and organic layers of the filtrate were separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving 1-methyl-3- (4-hydroxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione as a residue. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:24])[C:17](=[CH:20]OCC)[C:18]#[N:19])[CH3:14]>CCOCC>[CH2:13]([O:15][C:16]([C:17]([C:18]#[N:19])=[CH:20][N:2]([CH3:1])[CH:3]=[N:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:24])[CH3:14]
Reactant: CNC=Nc1ccc(C)cc1C
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(C#N)=CN(C)C=Nc1ccc(C)cc1C

Procedure:
48.6 g of N1 -methyl-N2 -(2,4-dimethylphenyl)-formamidine are dissolved in 100 cc of ether and a solution of 51 g of ethoxymethylene-cyanoacetic acid ethyl ester in 100 cc of ether is added at about 20° C. while stirring. The precipitated product is filtered off with suction after 5 hours. It is very pure. If desired it can be recrystallized from chloroform/petroleum ether (40°-80° C.). Yield 68 g, b.p. 140°-142° C. ##STR5##
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:58])([C:54]([F:57])([F:56])[F:55])[C:24]([F:53])([F:52])[C:25]([F:51])([F:50])[C:26]([F:49])([F:48])[C:27]([F:47])([F:46])[O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:27]([F:46])([F:47])[C:26]([F:48])([F:49])[C:25]([F:50])([F:51])[C:24]([F:52])([F:53])[C:23]([F:22])([F:58])[C:54]([F:57])([F:55])[F:56])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.03 g, 3.61 mmol) and 4-(2-(2-(tridecafluorohexyloxy) tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (2.68 g, 4.02 mmol; prepared from 1,4-dibromobutane and 2-(2-(tridecafluorohexyloxy) tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated essentially as described in Example 3 and further purified by recrystallization from cyclohexane/ethyl acetate to yield 1.85 g of purified product.
Reaction SMILES: S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O=[C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][C:29]#[N:30]>C1C=CC=CC=1>[C:29]([CH:28]=[C:27]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: N#CCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Temperature: 115 °C

Procedure:
TsOH—H2O (1 g) was added into a solution of N-Boc piperazine (50 g) and 3-oxo-3-phenylpropanenitrile (19.49 g) in benzene (200 ml). The reaction mixture was heated up to 115° C. for 16 hours and resultant water was collected by Dean-Stark trap. After the solution was concentrated, a residue was obtained and further purification using silica gel chromatography provided tert-butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, CD3OD) δ7.91 (m, 5H), 5.24 (s, 1H), 3.89-3.50 (m, 8H), 1.88 (s, 9H); 13C NMR (125 MHz, CD3OD) δ167.6, 155.7, 135.4, 130.6, 129.4, 121.8, 81.1, 67.1, 45.4, 28.0. MS m/z: (M+H)+ calcd for C18H24N3O2 314.19, found 314.25. Retention time 1.81 min (column D).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[C:9]2=[CH2:14])=[CH:4][CH:3]=1.[C:15]([OH:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(OCC)C>[C:15]([S:22][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C1C(=O)OCC1c1ccc(Cl)cc1
Reactant: OC(=S)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(SCC1C(=O)OCC1c1ccc(Cl)cc1)c1ccccc1
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 600 mg of β-(p-chlorophenyl)-α-methylene-γ-butyrolactone in 10 ml of toluene were added 0.44 ml of thiobenzoic acid and one drop of triethylamine and the reaction was effected at room temperature for 18 hours. The reaction mixture was diluted with 100 ml of ethyl ether, washed with water and saturated saline, dried over magnesium sulfate and the solvent was then distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 750 mg (yield 75%) of the title compound.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=O.[Cl:38][C:39]1[CH:64]=[CH:63][C:42]2[N:43]3[C:47]([CH2:48][NH:49][CH2:50][C:41]=2[CH:40]=1)=[N:46][N:45]=[C:44]3[CH:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:53][CH2:52]1>ClCCl>[NH3:3].[Cl:38][C:39]1[CH:64]=[CH:63][C:42]2[N:43]3[C:47]([CH2:48][N:49]([C:35](=[O:37])[CH2:34][CH2:33][O:32][CH3:31])[CH2:50][C:41]=2[CH:40]=1)=[N:46][N:45]=[C:44]3[CH:51]1[CH2:52][CH2:53][N:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[CH2:55][CH2:56]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCC(=O)O
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: N
Reaction time: 0.17 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.6 mmol) followed by 1-hydroxybenzotriazole hydrate (81 mg, 0.6 mmol) and triethylamine (84 μl, 0.6 mmol) were added to a solution of 3-methoxypropionic acid (63 mg, 0.6 mmol) in dichloromethane (10 ml) and the solution stirred for 10 minutes. The amine from example 4 (150 mg, 0.4 mmol) was added and the reaction stirred at room temperature for 5 hours. The reaction was washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) to give the title compound as a white solid, 166 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:22]1[CH:34]=[CH:33][C:32]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)[CH:18]=[CH:17]3.CN(C=O)C.[Br:43]N1C(=O)CCC1=O>O>[Br:43][C:15]1[C:4]2[CH:5]=[C:6]3[C:14]([C:2]([CH3:37])([CH3:1])[C:3]=2[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]([C:22]1[CH:34]=[CH:33][C:32]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([CH3:36])([CH3:35])[C:24]=4[CH:23]=1)[CH:20]=2)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7]3
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc5c(c4)C(C)(C)c4ccccc4-5)C=C32)C=C2N=c3ccccc3=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc4c(c3)C(C)(C)c3ccccc3-4)C=C12
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
The resulting 12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (7.0 g) and DMF (140 ml) were added to a reaction vessel. The mixture was heated up to 100° C., dissolved, and cooled. N-bromo-succinimide (2.6 g) was added under ice-cooled conditions, and the mixture was stirred for 1 hour at a room temperature. Water (500 ml) was added, and the mixture was subjected to filtration to obtain a pale red powder of 7-bromo-12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (5.7 g; yield 70.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[Cl-].[NH4+:30]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([NH2:30])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: [NH4+]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Agent: [Cl-]
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and ammonium chloride were coupled to give 119bp. LCMS (ESI) m/z: 401.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=[O:26])=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19]C2.[Cl:28]C1C=CC(C2CCNCC2)=CC=1.[ClH:41]>>[OH2:26].[OH2:26].[ClH:28].[ClH:41].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1
Product: O

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine and then by a conventional treatment using hydrochloric acid, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazole dihydrochloride dihydrate was obtained, m.p. 228-230° C.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13][C:14](=[O:29])[C:15]2[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=2[O:27][CH3:28])[CH2:3]1.COCCN(S(F)(F)[F:40])CCOC>>[F:40][CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13][C:14](=[O:29])[C:15]2[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=2[O:27][CH3:28])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(O)C1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(F)C1

Procedure:
The title compound, light yellow solid, MS: m/e=435.3 [(M+H)+], was prepared in accordance with the general method of example 17 from cis-N-[2-(3-Hydroxy-pyrrolidin-1-yl)-cyclohexyl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 24) and bis(2-methoxyethyl)aminosulfur trifluoride. The two diastereomers were not separated.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CCO>[BrH:10].[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCO
Product: Br
Product: O=[N+]([O-])c1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A solution of 2-piperazin-1-yl-ethanol (5.10 g, 38.4 mmol) in EtOH (30 mL) was cooled to 0° C. and treated portionwise with 1-bromomethyl-4-nitro-benzene (8.30 g, 38.4 mmol). The mixture was allowed to warm to RT and stir at that temperature for 3 h. The mixture was filtered, and the solid was washed with EtOH and air-dried to afford the title compound (9.72 g, 73%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O3, 266.1 (M+H). found 266.2.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]([F:32])([F:33])[C:21]1[CH:20]=[C:19]([S:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5])=[CH:12][CH:13]=2)[CH:24]=[CH:23][C:22]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid tert-butyl ester (24 mg, 0.0478 mmol, 1 eq.) in DCM (2 mL) is added triethylsilane (0.038 mL, 0.2392 mmol, 5 eq.) followed by TFA (2 mL). The mixture is stirred at room temperature for 2 h. After concentration, the crude product is purified by preparative RP LC-MS to give 3-[4-(2-Trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzylamino]-propionic acid: 1H NMR (CD3OD, 400 MHz) δ7.66 (s, 1H), 7.60 (d, 1H), 7.55–7.38 (m, 7H), 7.28–7.21 (m, 3H), 4.33 (s, 2H), 4.18 (s, 2H), 3.26 (t, 2H), 2.72 (t, 2H); MS (ES+): (446.1, M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].CCCCCC.Cl[CH2:31][CH2:32][O:33][CH2:34][CH2:35]Cl>CN(C)C=O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:4]=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:2]=1[N:1]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A solution of 5.5 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 50 ml of dry N,N-dimethylformamide was added dropwise to a solution of 1.8 g of sodium hydride in oil (prewashed with hexane) in 150 ml of dry N,N-dimethylformamide over 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, 3.2 g of bis(2-chloroethyl)ether was added dropwise. The mixture was stirred at room temperature for 2 hours, and then at 60° C. for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.0 g of 2-(2-methylphenyl)-3-morpholinoimidazo[2,1-a]isoquinoline (Compound 218) as a yellow oily material. To a solution of 2.0 g of the product in 80 ml of ether was added a saturated solution of hydrogen chloride in ether. Precipitated crystalline was collected by filtration, and washed with ethanol to give 1.1 g of the title compound as a yellowish white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[S-:23][CH2:24][CH3:25].[Na+].C(S)C.[H-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[S:23][CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CC[S-]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc2c(SCC)cc(C(=O)OC)nc12
Reaction time: 2 h

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (1.0 g) in dry dimethylformamide (50 mls) was added dropwise to a stirred solution of sodium thioethoxide [made by the addition of ethanethiol (0.773 g) to 50% sodium hydride in oil (0.6 g) in dry dimethylformamide (30 mls) under nitrogen]. The purple solution was stirred for 2 hours, poured into ethyl acetate and acidified with dilute hydrochloric acid. The organic layer was separated, washed with water, sodium bicarbonate solution and then dried. Evaporation of the solvent gave 0.8 g of the desired product which was recrystallised from cyclohexane to give 0.52 g of yellow needles mp 193°-195°.
Reaction SMILES: Cl[C:2]1([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:3]1.[NH:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.C([N:26]1CCOCC1)C>>[N:13]1([C:2]2[N:7]=[C:6]([N:18]3[CH2:23][CH2:22][CH2:20][CH2:19]3)[CH:5]=[C:4]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:3]=2)[CH2:17][CH2:16][NH:26][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: ClC1(N2CCCC2)N=CC=C(N2CCCC2)N1
Reactant: CCN1CCOCC1
Product: c1c(N2CCCC2)nc(N2CCNCC2)nc1N1CCCC1

Procedure:
A mixture of 10.0 g (34.7 mmoles) of 2-chloro-2,6-bis(pyrrolidino)pyrimidine, 11.95 g (138.8 mmoles) of piperazine and 150 ml of N-ethylmorpholine is boiled under reflux under nitrogen for 25 hours, then the solvent and excess piperazine are distilled off under environmental pressure. After adding 100 ml of water to the residue, water is distilled off until the head temperature reaches 100° C. After cooling down, the residue is distributed between 200 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The evaporation residue is purified by chromatography on a silica gel column. By using a 9:1 mixture of chloroform and methanol as eluent and recrystallizing the product from hexane, the title compound is obtained in a yield of 8.54 g (81.4%), m.p.: 152°-160° C.