Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=[O:11].[C:15](=O)([O-])[O-:16].[K+].[K+].C=O>C(O)C>[OH:16][CH2:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1[nH]c2ccccc2c1CO
Temperature: 25 °C

Procedure:
Ethyl indole-2-carboxylate (5.87 gm) in absolute ethanol (85 ml) was combined with potassium carbonate (4.3 gm) and 37% formaldehyde (2.6 gm) and heated to reflux for four days. The mixture was cooled to room temperature and the solvents removed on a rotary evaporator. The residue was dissolved in water (100 ml) and the water solution was washed with ether (2×50 ml). The aqueous solution was made acidic with 3.6 N sulfuric acid and the resulting mixture was extracted with methylene chloride (2×50 ml) and ether (2×50 ml). The combined organic layers were dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was dissolved in acetone and purified by preparative centrifugally accelerated radial thin layer chromatography on silica gel using 10% methanol in methylene chloride as eluant. The product was obtained as an off-white solid. Physical data are reported in Table I.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([Br:31])[CH:30]=1)[NH:27][C:26](=[O:32])[CH2:25]2>>[Br:31][C:29]1[CH:30]=[C:22]([F:21])[CH:23]=[C:24]2[C:28]=1[NH:27][C:26](=[O:32])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4c(Br)cc(F)cc43)c(C)c2C1=O
Yield: 78.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (62 mg, 78.2%) as an orange solid.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[N:23]1([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[N:23]1([C:27]2[C:32]([CH:33]([C:7]3[CH:8]=[N:9][N:10]([CH3:22])[C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[OH:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1c(Cl)ncnc1N1CCC1
Reactant: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(C(O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 74 μL, 0.185 mmol) was slowly added drop-wise to a −78° C. solution of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C14) (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL). The reaction mixture was allowed to stir at −78° C. for 1 hour, and then a solution of 4-(azetidin-1-yl)-6-chloropyrimidine-5-carbaldehyde (C12) (28.1 mg, 0.142 mmol) in tetrahydrofuran (1 mL) was added. Stirring was continued for 1.5 hours at −78° C., then water was added, and the reaction mixture was removed from the cooling bath. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluent: 94:5:1 dichloromethane/methanol/triethylamine) provided the product. Yield: 40 mg, 0.094 mmol, 67%. LCMS m/z 425.2, 427.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.17-2.26 (m, 2H), 3.72 (s, 3H), 3.89-3.97 (m, 2H), 4.23-4.31 (m, 2H), 6.32 (s, 1H), 7.58 (s, 1H), 7.79 (br d, J=8 Hz, 1H), 7.85 (s, 1H), 7.92 (br dd, J=8, 2 Hz, 1H), 8.58 (br d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:65][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-ethoxycarbonyl-(L)-valine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 200-203° C.; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:18].[OH-].[Na+].OO>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
200 g of a paste which contains 95 g of 4-aminoanthrone and also contains sulphuric acid, and which is obtained in accordance with the instructions of Example 2, are suspended in 1 l of water and neutralized with concentrated sodium hydroxide solution, and the 4-aminoanthrone is filtered off. It is equally possible to start from the corresponding amount of 4-aminoanthrone which has been obtained according to Example 5 or 6. The 4-aminoanthrone is now stirred into 1 l of water, 150 ml of potassium waterglass (d = 1.25) are added, the mixture is warmed to 60° C and 500 ml of 6% strength hydrogen peroxide solution are added dropwise in the course of 2 hours. This causes the color of the suspension to change from yellow to red. The mixture is stirred for a further 3 hours and is filtered, and the residue is washed until neutral. After drying, 100 g of 1-aminoanthraquinone of 90% purity (89% of theory) are obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:22]=[O:23])C>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:22]=[O:23])=[CH:12][N:13]2[CH3:16])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cn1ccc2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Phosphoryl chloride (5.87 ml, 63.0 mmol) was added in portions while stirring DMF (45 ml) at 0° C. After stirring at the same temperature for 20 minutes, the reaction mixture was added with a solution of 6-fluoro-1-methylindole (6.71 g, 45.0 mmol) in DMF (45 ml) at 0° C. The reaction mixture was stirred for further 0.5 hour. Ice water and 1N NaOH were added to the reaction mixture to neutralize the same, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 6-fluoro-1-methylindole-3-carbaldehyde (4.18 g, 52%) was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 71%). MS (ISN) 586.1 [(M−H)−]; mp 197° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[C:29]#[C:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]>CO.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1ccc2[nH]nc(C#CCN(C)C)c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1ccc2[nH]nc(CCCN(C)C)c2c1
Yield: 99.1 %

Procedure:
3-(3-dimethylamino-prop-1-ynyl)-1H-indazole-5-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide (7 mg) was stirred with 5 mg 10% Pd/CaCO3 in methanol under hydrogen (balloon). After two hours at room temperature the mixture was degassed with nitrogen, filtered through celite to remove the catalyst and the solution concentrated to give 7 mg of 3-(3-dimethylamino-propyl)-1H-indazole-5-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1.O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: Fc1ccccc1Br
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Temperature: 35 °C
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 40 g of 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine was dissolved in 200 ml of tetrahydrofuran, to which 44 g of magnesium turnings was added, and the mixture was vigorously stirred. The reaction vessel was cooled when a temperature of the reaction solution was raised to 35° C., and 16.7 g of 1-bromo-2-fluorobenzene was added dropwise to the reaction solution at 35° to 37° C. over the period of 10 minutes. After stirring at 30° to 35° C. for 2 hours, the reaction solution was ice-cooled, to which 100 ml of a saturated aqueous solution of ammonium chloride and 100 ml of water were added. The mixture was extracted with ethyl acetate (200 ml×2, 100 ml). Then, the extract was washed with water and an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=10:1 to 5:1) to give 22.4 g of (2S)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]#[N:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:13].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[ClH:13].[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=2)=[NH:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CNC(=O)Cc1ccccc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=N)NC(=O)Cc2ccccc2)cc1
Yield: 69 %

Procedure:
Synthesis of this compound was achieved by the method set forth in Example 1, Part II above with the use of phenylacetylcyanamide in place of 4-methylbenzoylcyanamide and using 4-t-butylaniline hydrochloride instead of 4-isopropylaniline hydrochloride respectively. Yield 69%; m.p. 182–186° C.; Purity 86% (HPLC); 1H-NMR (CD3OD) δ 1.38 (s, 9H, CH3), 3.84 (s, 2H, CH2), 7.3 (d, 2H, ArH), 7.3–7.45 (m, 5H, ArH), 7.6 (d, 2H, ArH).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CCO)cn4)nn23)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CCOS(C)(=O)=O)cn4)nn23)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (96 μl, 1.22 mmol) was added to an ice-cold solution of 2-{6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridin-3-yl}ethanol (250 mg, 0.62 mmol) and Et3N (173 μl, 122 mmol) in CH2Cl2 (50 ml) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 1 h, then diluted with CH2Cl2 (50 ml). The resultant solution was washed with H2O (50 ml), HCl (40 ml) and NaHCO3 solution (sat., 40 ml). The colourless solution was dried (MgSO4) and concentrated under reduced pressure. The resultant mesylate was used directly without any further purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 71 %

Procedure:
A mixture of 12 parts of trans-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-3-(trifluoromethyl)benzamide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was solidified on scratching in 2,2'-oxybispropane. The precipitated product was filtered off and dissolved in 135 parts of methylbenzene and 105 parts of 1,1'-oxybisethane. The supernatant liquid was decanted, washed twice with a dilute ammonium hydroxide solution and the product was extracted with methylbenzene. The aqueous phase was saturated with potassium carbonate and the product was extracted with methylbenzene. The combined organic layers were dried, filtered and evaporated in vacuo, yielding 6.43 parts (71%) of trans-N-(3-methoxy-4-piperidinyl)-3-(trifluoromethyl)benzamide; mp. 100.3° C. (interm. 9).
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 90 °C

Procedure:
In 50 ml dry DMF were combined 2.10 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 2.0 g milled anhydrous K2CO3 and 1.3 ml benzylbromide. The mechanically stirred mixture was heated under nitrogen at 90° C. for 18 hours. During the first 4 hours, 1 ml benzyl bromide was added every hour as TLC analysis indicated it was being consumed. For the work-up, the mixture was poured in excess water and extracted with DCM. The DCM layer was concentrated to an oil and the oil was purified on a silica column (flash chromatography) using DCM as an eluent. The product-containing fractions were combined and concentrated to a solid. The solid was recrystallized from EtOAc/hexanes and dried in a vacuum desiccator to yield 2.10 g of product, m.p. 162°-163.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6]([CH3:14])([C:10]3=C)[CH2:5][CH2:4][CH2:3]1.Br[CH2:17]C(O)=O>>[CH:2]([C:8]12[CH2:10][C:6]3([CH3:14])[C:7]([CH3:17])([CH2:13][CH2:12][CH2:9]1)[CH:3]2[CH2:4][CH2:5]3)([CH3:1])[CH3:15]
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Reactant: O=C(O)CBr
Product: CC(C)C12CCCC3(C)C1CCC3(C)C2
Yield: 134.7 %

Procedure:
In a 2 L four-necked flask, 1,000 g of longifolene (manufactured by Yasuhara Chemical Co., Ltd.) and 100 g of bromoacetic acid were placed and reacted at 170° C. for 18 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and with water and then refined by distillation. Thereafter, the refined product was placed in a 2 L autoclave together with 18 g of a palladium-carbon hydrogenation catalyst and subjected to hydrogenation (hydrogen pressure: 6 MPa, reaction temperature: 100° C., reaction time: 2 hours). After completion of the reaction, the catalyst was removed by filtration. The filtrate was subjected to fractional distillation to obtain 200 g of the desired 4-isopropyl-1,7a-dimethyl-octahydro-1,4-methano-indene (Fluid 3). The results of the measurements of the properties and the traction coefficient are shown in Table 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCCCBr
Reactant: c1csc(CNCc2cccs2)c1
Product: N#CCCCN(Cc1cccs1)Cc1cccs1

Procedure:
In a manner analogous to Example 21 a, 4-[N, N-bis-(2-thienylmethyl )amino]butyronitrile was prepared by alkylation of bis-(2-thienylmethyl)amine using 4-bromobutyronitrile.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][C:14]=1[CH2:27][CH3:28].CN(C)[CH:31]=[O:32].[NH4+].[Cl-]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:31]=[O:32])=[C:14]([CH2:27][CH3:28])[CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=O
Reactant: CCc1cc(OCc2ccccc2)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(OCc2ccccc2)ccc1C=O
Temperature: -85 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 1.6 M solution of n-BuLi in hexane (44.4 ml, 69.9 mmol) was added within 10 min to a stirred cooled (−85° C.) solution of 1-bromo-2-ethyl-4-(phenylmethoxy)-benzene (18.5 g, 63.5 mmol) in dry THF (22 ml). The mixture was stirred for 1 h at −85° C. under an argon atmosphere. N,N-Dimethylformamide (25.5 ml, 330.4 mmol) was added and the temperature was allowed to rise slowly to room temperature. An aqueous saturated NH4Cl solution (70 ml) was added under ice cooling. The mixture was extracted two times with dichloromethane, the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 11.9 g (49.5 mmol, 78%) of the title compound as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])[CH:18]=[CH:17][CH:16]=1>CCO>[OH:14][CH:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2cccnc12
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 18 %

Procedure:
1-amino-3-(isoindolin-2-yl)propan-2-ol (50 mg, 0.26 mmol) and ethyl 2-(quinolin-8-yloxy)acetate (60 mg, 0.26 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (17.2 mg, yield 18%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.95-8.87 (m, 1H), 8.45-8.36 (m, 1H), 7.67-7.56 (m, 3H), 7.35-7.25 (m, 1H), 7.24-7.12 (m, 4H), 4.83-4.76 (m, 2H), 4.09-4.03 (m, 1H), 4.02-3.95 (m, 4H), 3.60-3.54 (m, 1H), 3.46-3.40 (m, 1H), 2.92-2.86 (m, 1H), 2.84-2.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][NH2:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: [H][H]
Reactant: N#CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Yield: 92.6 %

Procedure:
10 g of 1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbonitrile (step 1 of preparation example 1) was dissolved in 200 ml of methanol and 50 ml of ammonia (7N solution in methanol) was added, followed by 3 g of Raney Nickel. The reactor was sealed and the reaction mixture was stirred under 3 bar of hydrogen at ambient temperature for 2 hours. Then additional 5 g of Raney Nickel were added and the reaction mixture was stirred under 3 bar of hydrogen at ambient temperature for another 15 hours. Then the reaction mixture was filtered over celite and the filtrate was concentrated. Thus, 9.41 g of crude C-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-methylamine was obtained as an orange oil, which was used for the next step without further purification. 1H-NMR (CDCl3): 8.72 ppm (s, 1H), 7.90 ppm (s, 1H), 3.00 ppm (s, 2H), 1.10 ppm (s, 2H, broad), 1.00 ppm (m, 2H), 0.90 ppm (m, 2H).