Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:33])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)=[CH:18][C:17]1=[O:33]
Reactant: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of hydrochloric acid (3.0 mL, 4.0 M in 1,4-dioxane) was added dropwise to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[4-(1H-pyrazol-1-yl)phenyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (58 mg, 0.11 mmol) in dichloromethane (3.0 mL) and methanol (0.6 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether, filtered, washed with heptane, and dried under reduced pressure to provide a light yellow solid (47 mg, 98%). MS (APCI) m/z 431.3 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 1.71 (s, 3H), 2.36-2.43 (m, 1H), 2.59-2.68 (m, 1H), 3.09 (s, 3H), 3.96-4.05 (m 1H), 4.30-4.40 (m, 1H), 6.56 (dd, J=1.8, 2.3 Hz, 1H), 6.93-6.95 (m, 2H), 7.76 (d, J=1.8 Hz, 1H), 7.82-7.92 (m, 5H), 8.31 (d, J=2.3, 1H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[K+].Cl[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(C)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNCC(=O)O
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN(CC(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a 250 ml three-necked flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a condenser, a mixture of sarcosine (4.45 g; 50 mmol) and KOH (8.47 g; 151 mmol) in 70 ml of isopropanol is prepared by heating the mixture to 50° C. The medium remains cloudy after 30 minutes then chlorodiphenylmethane (10.7 ml; 60 mmol) is added over 30 minutes at 50° C. The mixture is heated for 5 hours at this temperature. The mixture is then left to cool down to ambient temperature. After the addition of 100 ml of water, the pH is adjusted to 10 and the chlorodiphenylmethane which has not reacted is recovered after extraction with CHCl3. The pH is adjusted to 5-6 with concentrated HCl and the mixture is extracted once again with chloroform in order to produce 2.23 g of product (Yield=18%) in the form of colourless gum.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Mg].[Cl-].[NH4+]>CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([C:2]([F:7])([F:6])[F:1])([OH:4])[CH3:5])=[CH:10][CH:11]=1
Reactant: CC(=O)C(F)(F)F
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
1,1,1-Trifluoroacetone (60.4 ml; 675 mmol) dissolved in absolute ether (80 ml) was added, dropwise, at 5° to 10° C. to an ethereal Grignard solution (prepared from p-bromoanisole (84.17 g; 450 mmol) and magnesium (10.9 g; 450 mmol) in ether (600 ml)) and the mixture stirred at room temperature for 20 hours. It was then added to saturated ammonium chloride solution, extracted with ether and the extract washed with water, dried over sodium sulphate and concentrated. The precipitate was filtered off washed with hexane and the filtrate concentrated. 1-(4-methoxyphenyl)-1-trifluoromethylethanol (93.35 g=94.2% of theory) was obtained as a brown oil that was used without further purification. (The alcohol can also be coverted direct to the nitrile in a one-pot reaction.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1>C(OCC)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:13]([F:19])=[CH:14][C:15]([CH3:18])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[N:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S(=O)(=O)Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.91 g (25 mmol) of chlorosulfonic acid and then 1.3 g (5 mmol) of 4-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-3-fluorotoluene. The mixture was stirred at 80° C. for 3 hours and cooled to room temperature. The mixture was added onto ice in small portions, and 30 ml of ethyl acetate was added to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to vacuum distillation to distil off ethyl acetate, to obtain a title compound as 1.66 g of a crystal. Yield: 93%
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.N([O-])=O.[Na+].Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([SH:35])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C=O.[Cu]>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:25]=[C:24]([S:35][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=3)[NH:23][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(F)cc1
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccc(F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 38 %

Procedure:
At 0° a diazonium salt solution prepared from 2.5 g of 4-fluoroaniline, 1.58 g of sodium nitrite, and 10 ml of 6 N hydrochloric acid is added dropwise to a solution of 6.25 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in a mixture of 240 ml of dimethylformamide, 10 ml of 2 N sodium hydroxide solution, and 1.45 g of pulverized copper. The solution assumes a reddish brown color under evolution of nitrogen. The mixture is agitated for another 3 hours, the solution is concentrated under vacuum, and the residue is distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is chromatographed over a column on 500 g of silica gel. Elution with acetone/hexane 2:3 yields 3.09 g of 4,5-bis(4-methoxyphenyl)-2-(4-fluorophenylthio)imidazole, mp 106° after recrystallization from hot diisopropyl ether/methylene chloride.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=3[F:37])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2c(F)cccc2F)ccc2cc(O)ccc12
Yield: 54 %

Procedure:
Convert [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-methanone (2.5 g, 4.8 mmol) into the hydrochloride salt and charge a flask with the solid salt. Dissolve the material in 200 mL methylene chloride and chill in ice. Add to this mixture boron tribromide (5.0 mL, 53.0 mmol) while swirling. Stir the reaction at room temperature for one hour and pour into a two phase system of saturated sodium bicarbonate and an organic layer consisting of a 3/1 mixture of chloroform/isopropanol. Shake to extract the product, separate the organic layer, dry over 3 Å molecular sieves and evaporate the solvent under vacuum. Purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (54%) of the title compound: 1H-NMR (CDCl3, 400 MHz) δ 7.79-7.74 (d, 1H); 7.58 (d, J=8.4 Hz, 2H); 7.50 (d, J=8.8 Hz, 1H); 7.33-7.30 (d, 1H); 7.17 (d, J=2.4 Hz, 1H); 7.16-7.08 (m, 1H); 6.99-6.95 (dd, 1H); 6.77-6.73 (m, 2H); 6.68 (d, J=9.2 Hz, 2H); 4.11 (t, J=6.0 Hz, 2H); 3.05-2.99 (t, 2H); 2.90-2.84 (m, 4H); 1.71-1.71 (m, 4H); 1.63-1.60 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1(O)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[CH2:1]=[C:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1C2CC3CC(C2)CC1C3
Yield: 98 %

Procedure:
One liter flask equipped with a Dean-Stark condenser was charged-with 166.3 g (1.0 mol) of 2-methyl-2-adamantanol (supplied by Sigma-Aldrich Co.), 2.0 g (20 mmol) of sulfuric acid and 500 g of toluene. The content was heated to the solvent reflux temperature. While toluene and water produced through the reaction were collected as an azeotrope by the Dean-Stark condenser, the reaction mixture was refluxed for 2 hours. After completion of the reaction, the catalyst was removed by washing the reaction mixture with water and the obtained organic phase was concentrated to dryness to give 152.5 g of white solid 2-methyleneadamantane (purity: 99.0%, yield: 98.0%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:7]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Yield: 86 %

Procedure:
By reacting 6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4, the title product is obtained in a yield of 86.0%, m.p.: 120°-124° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:11]=[C:10]([I:12])[CH:9]=2)[C:5](=[O:14])[C:6]1=[O:13]
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-trifluoromethyl-6-iodo-1H-indole-2,3-dione (12.0 g, 35.2 mmol) in N,N-dimethylformamide (120 mL) was cooled to 0° C. under nitrogen, and thereto was added 55% sodium hydride (1.70 g, 39.0 mmol) and the mixture was stirred for 30 minutes. Then, to the reaction solution was added dropwise 2-(trimethylsilyl)-ethoxymethyl chloride (7.00 mL, 39.6 mmol), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate-toluene (1:1) twice, washed with water twice, and then dried over magnesium sulfate, and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the titled compound (13.7 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:46])[C:30](=[O:45])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:36]1)=[O:34].[CH3:47][N:48]=[C:49]=[O:50]>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:46])[C:30](=[O:45])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][N:42]([C:49]([NH:48][CH3:47])=[O:50])[CH2:41]2)[CH2:36]1)=[O:34]
Reactant: CN=C=O
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCNC5)C4)c3Cl)cccc2n1Cc1ccccn1
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CCC(C(=O)NCC(=O)N(C)c3ccc(Cl)c(COc4cccc5c4nc(OC)n5Cc4ccccn4)c3Cl)C2)C1
Temperature: 25 °C

Procedure:
A solution of N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)-[1,3′-bipyrrolidine]-3-carboxamide (0.20 g, 0.3 mmol) in dichloromethane (15 ml) was treated with methyl isocyanate (0.023 mL, 0.39 mmol) with stirring at room temperature for ten minutes. The reaction was evaporated, treated with methanol and evaporated to a tan solid, 0.20 g. This residue was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford 24 as a white solid, 0.06 g (28%), that was pure by LC/MS (+ESI) m/z 723 (M+), and was pure by 1HNMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.59 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.19 (m, 1H), 7.05 (m, 1H), 6.80 (m, 2H), 5.69 (s, 2H), 5.29 (s, 2H), 4.20 (m, 4H), 3.80 (m, 1H), 3.50 (m, 3H), 3.25 (m, 5H), 2.85 (m, 7H), 2.55 (m, 2H), 2.10 (m, 5H). 13CNMR (100 MHz, CDCl3) δ 150, 148, 131, 130, 121, 122, 123, 108, 103, 65, 63, 58, 57, 51, 50, 48, 43, 42, 41, 35, 31, 30, 29, 28. Anal. Calcd for C15H21N3O3+1.0H2O: C, 56.68; H, 5.71; N, 15.11. Found: C, 56.73; H, 5.51; N, 14.82.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:14]1[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=1)([CH3:13])[CH2:5][CH2:6][O:7]2.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:14]1[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=1)([CH3:13])[CH2:5][CH2:6][O:7]2
Reactant: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.21 mmol) of the compound from Example 193 were introduced into 10 ml of dichloromethane at 0° C., 51 mg (0.21 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient).
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].ClCCl.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:19]([O:18][C:16]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CC)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
183 mg (0.64 mmol) of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate are diluted in 4 mL of an 8/2 dichloromethane/trifluoroacetic acid mixture. The solution is stirred at room temperature for 1 hour and the solvents are then evaporated off. 140 mg of 4-ethoxycarbonyl-4-ethylpiperidine trifluoroacetate in the form of an oil are obtained in a yield of 73%.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5]([CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19])[CH3:4].C=O.[C:24]([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH2:20]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19])[CH3:24])[CH3:21]
Reactant: CCN(CC)CCCNCc1cc(I)cc(C)c1O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCCN(C)Cc1cc(I)cc(C)c1O

Procedure:
Reductive methylation of N[3(Diethylamino)propyl]-2-hydroxy-3-methyl-5-iodo-benzylamine dihydrochloride (5 mmol, from last step) formaldehyde (5 mL, 37% solution) and sodium cyanoborohydride (0.63 g, 10 mmol) in methanol (25 mL), work-up, conversion to the dihydrochloride (conc. hydrochloric acid, 5 mL), evaporation to dryness in vacuo and crystallization of the resulting material from methanol-acetone as described for Example 1 gave the title compound as colorless crystals. Yield(overall): 1,945 g (84%); mp. 166°-168° C. NMR (CDCl3, free base): δ0.97 (t, 6H, J-6 Hz, --CH2 --CH3); 1.5-1.9 (m, 2H, --CH2 --); 2.13 (s, 3H, --CH3); 2.23 (s, 3H, --CH3); 2.3-2.7 (m, 8H, N--CH2); 3.6 (s, 2H benzylic CH2), 7.1 (d, 1H, J=1 Hz, aromatic H); 7.35 (d, 1H, J=1 Hz, aromatic H); IR (KBr): 3420, 2940, 2640, 1625, 1470, 1390, 1210 cm-1. Analysis found: C, 41.47; H, 6.24; N, 5.93. C16H29Cl2IN2O requires: C, 41.49; H, 6.31; N, 6.05.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]12[CH2:14][CH:13]1[C:12](=[O:15])N[C:10]2=[O:16]>>[CH2:1]([N:8]1[C:12](=[O:15])[CH:13]2[CH:9]([CH2:14]2)[C:10]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C2CC12
Reactant: NCc1ccccc1
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
Benzylamine (2.5 mL, 22.3 mmol) was added drop wise to ice cooled 3-aza-bicyclo[3.1.0]hexane-2,4-dione (2.5 g, 22.3 mmol) then the mixture was heated to 170° C. with stirring for 1.5 h. After cooling to room temperature, the resulting mixture was crystallized from isopropanol to give 3-benzyl-3-aza-bicyclo[3.1.0]hexane-2,4-dione (3.72 g, 83%) as a white solid. LC-MS: [M+H]+, 202.1, tR=1.478 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.F[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=2)[CH2:24][CH2:25][CH2:26]1)=[O:9]
Reactant: O=C(O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Reactant: Fc1ccc2c(c1)CCCN2
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)ccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 110, Step 2, replacing 2-(2,5-dichloro-phenoxy)-benzoic acid (Example 110, Step 1) with 2-(2,5-dichloro-phenoxy)-5-fluoro-benzoic acid and 6-fluoro-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 416.1 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[C:14](OCC)=[O:15]>C(O)C>[N:6]1[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[C:14](=[O:15])[NH:7][CH:5]=1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2cc[nH]c12
Yield: 85.2 %

Procedure:
Formamidine acetate (20 g, 0.19 mol.) was added to a solution of crude 2-ethoxycarbonyl-3-aminopyrrole (14) (15.3 g, 0.1 mol.) in ethanol (150 ml) and the solution was heated under reflux for 16 h and then cooled. The solid formed was filtered, washed with ethanol and dried to give 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (1) (11.5 g, 85.2 mmol.). Recrystallized from water it had mp>300° C. 1H NMR (d6-DMSO) was as reported3. 13C NMR δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][CH2:9][C:4]=2[Se:5][C:6]=1[C:7]#[N:8].[OH-:13].[Na+].O>C(O)C>[NH2:1][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][CH2:9][C:4]=2[Se:5][C:6]=1[C:7]([NH2:8])=[O:13]
Reactant: N#Cc1[se]c2c(c1N)CCCC2
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1[se]c2c(c1N)CCCC2
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a suspension of 3-amino-4,5,6,7-tetrahydrobenzo[1,2-b]selenophene-2-carbonitrile (2.4 g) in ethanol (50 mL) was added aqueous sodium hydroxide solution (50 mL, 10%) at rt and the mixture was refluxed for 1 h. The cooled reaction mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid filtered, washed with cold water and dried to give the product as a pale brown color solid (1.4 g, 54%), mp 152-154° C. 1H NMR (400 MHz, DMSO-d6): δ 6.58 (1H, s, —CONH2), 6.45 (1H, s, —CONH2), 2.66 (2H, s, H-7), 2.24 (2H, s, H-4), 1.73 (4H, s, H-5,6); LC-MS (positive ion mode): m/z 265, 267 (M+Na)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl[C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([NH:2][C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cn2)CC1
Reactant: COC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of methyl [trans-4-(5-aminopyridin-2-yl)cyclohexyl]acetate hydrochloride, prepared as above, (831 mg, 2.59 mmol) in DCM (50 mL) was added triethylamine (1.3 mL, 9.31 mmol) followed by methyl chlorooxoacetate (0.31 mL, 3.36 mmol) and the reaction mixture was allowed to stir at O—C for 2 hrs. The reaction mixture was diluted with DCM (100 mL) and washed with water (80 mL) then brine (80 mL) and the aqueous layer was re extracted with DCM (50 mL). The organic washings were combined, dried and concentrated to give the title compound, 865 mg (2.59 mmol, 100%) which was taken through to the next stage; 1H NMR (CDCl3) δ 1.13-1.27 (m, 1H), 1.57-1.64 (m, 3H), 1.84-2.00 (m, 5H), 2.26 (d, 2H), 2.62-2.70 (m, 1H), 3.68 (s, 3H), 3.98 (s, 3H), 7.18 (d, 1H), 8.13 (d, 1H), 8.60 (s, 1H), 8.82 (brs, 1H); MS m/e MH+ 335.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][CH:12]([CH2:23][CH3:24])[C:13]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[C:6]([Cl:25])[N:5]=1.[C:26]1(C)[CH:31]=CC=C[CH:27]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]([CH2:31][C:26]#[CH:27])[C:14](=[O:16])[C:13]([CH2:21][CH3:22])([C:17]([O:19][CH3:20])=[O:18])[CH:12]([CH2:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([Cl:25])[N:5]=1
Reactant: Cc1ccccc1
Reactant: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(CC)(C(=O)OC)C(CC)N=C1c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To 3.15 g (78 mmol) of sodium hydride in 50 mL of dimethylformamide at 0° C. was added dropwise over 1.5 hr a solution of 26.9 g (75 mmol) of 2-(2,6-dichloro-4-pyridyl)-5,6-diethyl-5-methoxycarbonyl-5,6-dihydropyrimidin-4-one in 200 mL of dimethylformamide. When this addition was complete 12.5 mL (16.73 g, 112.5 mmol) of 80% propargyl brmide in toluene was added and the reaction stirred at room temperature overnight. Upon completion the reaction was quenched onto 600 mL of ice/water, extracted with ethyl acetate (3×400 mL), the organics were combined, washed with water (2×300 mL) and saturated sodium chloride (2×500 mL), dried over Na2SO4, filtered and evaporated to dryness in vacuo to give 29.23 g (73.8 mmol, 98%) of the desired product as a yellow solid.