Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:72])[C:65]([C@@H:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][C@H:67]1[C:65]([N:64]([CH3:72])[CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3C(=O)N(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-dimethylaminocarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH3:19][NH2:20].[C-]#N.[Na+]>CO>[NH2:1][C@H:2]([C:15]([NH:20][CH3:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CN
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.6 g (42.0 mmol) of Tyr(3-tBu)-OMe in 80 ml of methanol, 80 ml of a solution of 40% methylamine in methanol and 0.41 g of sodium cyanide were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with water, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to give Tyr(3-tBu)-NHMe in the amount of 7.3 g (70%).
Reaction SMILES: [C:1]([N:4]([CH2:14]C)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:16](Cl)(=O)CC>C1C=CC=CC=1>[C:1]([N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH2:2][CH3:16]
Reactant: CCN(C(C)=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Solvent: c1ccccc1
Product: CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
The reaction is carried out using an analogous method to (9a), using N-methyl-4 nitroanilinc (5 g, 32.86 mmol) in benzene (30 ml), treated with propionyl chloride (15 ml). ES+ (M+1) 208.88.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: CON
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Agent: Cl
Product: CON=C(CN1CCCC1=O)c1cccnc1
Yield: 70 %

Procedure:
0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20 and 0.18 g (2.21 mmol) of methoxyamine hydrochloride salt were treated as described in Example 22 to obtain 0.24 g (70% yield) of 1-(2-methoxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (2.38:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[CH3:10][O:9][C:3]1[C:4]([O:8][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: COc1c(O)cccc1Br
Reactant: C1=COCCC1
Product: COc1c(Br)cccc1OC1CCCCO1

Procedure:
Treatment of 3-bromo-2-methoxyphenol with dihydropyran and an acid catalyst as described herein affords 2-methoxy-3-tetrahydropyranyloxy-1-bromobenzene.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH:21]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(C)C(S([NH:48][N:49]=[C:50]([CH3:54])[CH:51](Cl)Cl)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:18][CH:17]=[C:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([N:5]3[CH2:4][C@H:3]([CH2:2][N:1]4[CH:51]=[C:50]([CH3:54])[N:49]=[N:48]4)[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:29])[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Yield: 46.7 %

Procedure:
(5S)-5-(Aminomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-diflurophenyl]-1,3-oxazolidin-2-one (Intermediate 54) (3.20 g, 8.01 mmol) was reacted with diisopropylethylamine (5.60 ml, 32.04 mmol) and 1,1-dichloroacetone toluenesulfonylhydrazone (2.8 g, 9.6 mmol) as described for Example 3. Chromatography on silica gel with ethyl acetate gave 1.74 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:36])[CH3:35])[CH2:29][CH:28]2[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH3:47])[CH:38]=2)=[O:7])=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: CCOc1cc(C2CC(OC(C)=O)CCC2N)ccc1OC
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OC)nc2OC)ccc1OC
Temperature: 40 °C
Reaction time: 42 h
Yield: 102.6 %

Procedure:
555 mg of 2,6-dimethoxynicotinic acid and 581 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are placed in a flask under nitrogen. 778 mg of acetic acid (1RS,3RS,4RS)-4-amino-3-(3-ethoxy-4-methoxyphenyl)cyclohexyl ester (compound B1) and 2 mg of 4-dimethylaminopyridine both as solution in dichloromethane are added and the solution stirred for 1 h at 40° C., than 42 h at room temperature. The reaction is quenched with 5 ml of water. After phase separation the organic layer is washed with 2.5 ml of saturated potassium hydrogencarbonate solution. After drying the organic layer with magnesium sulfate the solvent is removed to give 1.227 g of the crude title compound which are used for the following step without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:59])[CH2:43][N:44](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:38][C:37]=1[NH:60][S:61]([CH3:64])(=[O:63])=[O:62])C1C=CC=CC=1>>[OH:59][CH:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.00 (m, 5H), 3.16 (s, 3H), 3.55-3.70 (m, 2H), 4.65-4.80 (m, 1H), 6.00 (brs, 1H), 6.70-7.25 (m, 7H), 7.58 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 10.39 (s, 1H); MS (ES) m/z: 618.1 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2036.
Reaction SMILES: O1CCO[CH2:3][CH2:2]1.Br[C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:31])([CH3:30])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1.CCCCCC.C([Zn]CC)C>O>[CH2:2]([C:8]1[CH:33]=[N:32][C:11]2[O:12][C:13]([CH3:30])([CH3:31])[C:14](=[O:29])[N:15]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[CH:9]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ncc(Br)cc32)CC1
Reactant: C1COCCO1
Agent: CC[Zn]CC
Solvent: O
Solvent: CCCCCC
Product: CCc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Reaction time: 8 h

Procedure:
At room temperature, to a 1,4-dioxane solution (10.0 ml) of tert-butyl 4-(7-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (Example 52-1) (150 mg) was added a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (69.5 mg), and then a hexane solution (1 M, 0.681 ml) of diethyl zinc was added dropwise, followed by stirring overnight. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (84.8 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Cl[CH2:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[N:15]=2)[N:3]=1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (11.0 g, 41.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (10.0 g, 41.4 mmol) and K2CO3 (6.0 g, 43.4 mmol) in DMSO (60 mL) was stirred at room temperature overnight. Then the mixture was added H2O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE:EtOAc=2:1) to give 141 (10.0 g, yield 52%) as a yellow solid. LCMS (ESI), M+H+=466.04. 1HNMR (400 MHz, CDCl3) δ 5.783 (s, 2H), 5.785 (s, 2H), 7.068-7.090 (q, J=0.8 Hz, 1H), 7.088-7.307 (m, 3H), 7.362-7.422 (m, 4H), 7.800-7.822 (d, J=0.8 Hz, 1H), 8.219-8.221 (d, J=1.2 Hz, 2H)
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[C:19]1([S:25]([NH2:28])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C@@H]1(N)CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH2:18][C:3]1[C:2]([NH:28][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[N:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(NS(=O)(=O)c3ccccc3)n2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 6.3 %

Procedure:
3-bromo-5-(4-methylsulfonylphenyl)pyrazin-2-amine (0.05 g, 0.152 mmol), benzene sulfonamide (0.12 g, 0.762 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.017 g, 0.152 mmol), cuprous iodide (0.058 g, 0.305 mmol) and K2CO3 (0.042 g, 0.305 mmol) were combined together in dioxane (4 mL) and heated for 15 minutes under microwave conditions at 120° C. and then 140° C. for a further 20 minutes. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and water. The layers were separated and the aqueous further extracted with DCM. The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo. This material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (3.9 mg, 3.65% Yield). H1 NMR (400.0 MHz, DMSO) δ 8.34 (s, 1H), 8.04-8.01 (m, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.67-7.64 (m, 3H) and 3.23 (s, 3H). MS (ES+) 405.0
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11](#[N:14])C=C.C1(C=CC(O)=CC=1)O>>[C:11]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)#[N:14]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC#N
Agent: Oc1ccc(O)cc1
Product: N#CC12C=CC(CC1)C2
Reaction time: 7 h

Procedure:
Dicyclopentadiene of 54.2%, acrylonitrile of 45.8% and hydroquinone of 500 ppm as a polymerization inhibitor were mixed, and this mixed solution was continuously fed into a tubular reactor (inner diameter: 8 mm) at a rate of 50 ml/hr, wherein the reaction temperature was controlled to 153° C. in a residence time of the reaction solution of up to 5 hours, 170° C. in a residence time of up to 7 hours and 180° C. in a residence time of up to 9 hours. After this reaction reached a steady state, the reaction was further continued for 20 hours to obtain crude cyanonorbornene of about 1 liter having a purity of 95%. This was concentrated under reduced pressure to distill off unreacted cyclopentadiene and acrylonitrile, whereby cyanonorbornene of 950 g having a purity of 99.6% was obtained.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:9]([CH3:11])[CH3:10].C(O)(C)C>O.S([O-])(O)(=O)=O.[Na+]>[CH:9]([O:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:11])[CH3:10]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: O=C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 84.12 grams (1 mol) of cyclopentanone, 195.2 grams (1.03 mol) of triisopropyl orthoformate and 60 grams of isopropanol (1 mol) was stirred in a 500 ml three-neck round bottom flask at room temperature. To this mixture, 3.8 g (0.028 mol) of sodium hydrogensulfate monohydrate was added, and the temperature of the reaction mixture was heated and maintained at 40° C. for about one hour. The progress of the reaction was monitored by GC until the cyclopentanone content was reduced to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure while the temperature of the reaction mixture was increased to a maximum of 65° C. The reaction mixture was cooled to room temperature and the pH value was adjusted to about 7˜8 by adding about 0.2 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclopentanone and 64 grams (0.51 mol) of 1-isopropoxy-1-cyclopentene was isolated as a clear liquid at a yield of 51%. The purity of the product exceeded 98%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[C:10]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.O.O.[Rh](Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#CCc1ccncc1
Agent: Cl[Rh](Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C#N)c1ccncc1
Yield: 313.5 %

Procedure:
4-Pyridylacetonitrile (5.6 g, 47.46 mmol) dissolved in ethanol (70 ml) was heated under reflux with rhodium chloride trihydrate (624 mg, 2.37 mmol), triphenylphosphine (3.11 g, 11.87 mmol) and anhydrous sodium carbonate (5.534 g, 52.2 mmol) for 20 hours, filtered and concentrated. Elution from a column (4.5, 35 cm) of silica gel (Merck 7734) with CHCl3 afforded a pure fraction of 2-(4-pyridyl)butyronitrile (5.44 g, 78.5% yield). This was taken up in t-butanol (15 ml) and stirred with `Triton B` (0.2 ml) and acrylonitrile (2.5 ml, 58 mmol) for 2 hours. Excess solvent was evaporated and the residue was diluted with water (200 ml). Extraction from CHCl3 (2×100 ml) afforded impure 2-ethyl-2-(4-pyridyl)butyronitrile which was heated under reflux with a mixture of glacial acetic acid (30 ml) and concentrated sulphuric acid (6 ml) for 3 hours and poured onto ice water. Sodium hydrogen carbonate was added to neutralise the solution, to pH 7-7.5 and the solution was then extracted with CHCl3. Column chromatography (3×20 cm, silica gel, CHCl3 :MeOH 19:1 v/v) of the crude product afforded a pure fraction of the title compound, (3.29 g), in a 40.2% yield based on 2-(4-pyridyl)butyronitrile. The title compound was crystallised from toluene, m.p. 138-139° (corrected).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[CH3:12][C:13]([CH3:15])=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](=[C:13]([CH3:15])[CH3:12])[C:6]#[N:7]
Reactant: COc1ccccc1CC#N
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(C#N)=C(C)C

Procedure:
According to the procedure described by Example 1, o-methoxybenzylcyanide (18.6 g, 127 mmol) is condensed with acetone (50 ml) under addition of methanol (6.5 ml) and KOH (3.33 g, 50 mmol) to yield, after workup and distillation at 106-110° C./0.05 mbar, 2-(2-methoxyphenyl)-3-methyl-but-2-ene nitrile (1.7 g, 7%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)[CH:24]=[N:25][CH:26]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: COc1cncc(Br)c1
Product: COc1cncc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 3-bromo-5-methoxy-pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cccc2cc[nH]c12
Temperature: 0 °C
Yield: 56.1 %

Procedure:
To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at −78° C. was added 'BuLi (1.7 M, 33.8 mL, 57.4 mmol) and the mixture was allowed to warm to 0° C. The reaction was re-cooled to −78° C. and a solution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and the reaction was allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 7-(methylthio)-1H-indole (1.4 g, 55%). 1H NMR (400 MHz, CDCl3) δ=2.50 (s, 3 H), 6.58 (dd, J=3.03, 2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.83 (d, J=7.83 Hz, 1H), 8.45 (br. s., 1 H); MS (ES+): m/z 164.15 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:23][CH2:24][CH2:25][C:26]#[N:27]>O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:23][CH2:24][CH2:25][C:26]#[N:27]
Reactant: N#CCCCBr
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 3-dimethylaminophenol (5 g), potassium carbonate (10.05 g) and dimethylformamide (85 ml) was stirred at room temperature for 5 hours. 4-Bromobutyronitrile (7.3 ml) was added and the suspension stirred for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to yield 4-(3-dimethylaminophenoxy)butyronitrile.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: NCCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCCN(Cc1ccccc1)c1ccccn1
Yield: 36.3 %

Procedure:
Sodium hydride (1.6 g) was disolved in DMSO (35 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(4-aminobutylamino)pyridine (10 g) in DMSO (10 ml) added at room temperature. Benzyl bromide (10.35 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-30° C. After a further 2 hr water (200 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid and the aqueous layer basified to pH 4. After extracting with chloroform the pH was raised to 14 and again extracted with chloroform. After stripping the latter extract the residue was taken up in ether and the solution washed with water. The ether layer was dried (K2CO3) and stripped to give 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (5.61 g) as an oil which was used without further purification. (ii) 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (1 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.82 g) were heated together under reflux in pyridine (5 ml) for 22 hr. After cooling the mixture was stripped, the residue triturated with ether and crystallised from ethanol/ether to give 2-[4-(N-benzyl-N-pyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 0.4H2O, 1.15 g (80%) mp softens 98°-100° C. melts 120°-22° C. (from ethanol/water).