Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][NH2:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>C(#N)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([CH2:18][NH:9][CH2:8][CH2:7][NH2:10])=[CH:16][CH:17]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NCCNCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 4.2 g (0.03 mol) of potassium carbonate and 10 ml (0.15 mol) of ethylenediamine in a 50 ml of flask placed in an ice bath, 4.8 g (0.03 mol) of 2-chloro-5-(chloromethyl)pyridine dissolved in 15 ml of acetonitrile was added dropwise and slowly for nearly 20 min. After addition, the ice bath was removed and then the mixture was stirred for 8 hours at room temperature. After the reaction was stopped, a large amount of water was added to dissolve potassium carbonate and ethylenediamine, and the mixture was extracted with dichlormethane. The lower organic phase was collected, dried, and evaporated to dryness (It was better to remove all of the ethylenediamine in the solvent since its presence would influence the following step). The obtained product was yellow oily liquid in 68% yield.
Reaction SMILES: N1C=CN=[CH:2]1.C(O[C:9]([C:11]1[N:16]2N=[C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])[N:19]=[C:15]2[CH:14]=[C:13]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=1)=[O:10])C.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:24]([NH:23][C:21]([NH:20][C:18]1[N:19]=[C:15]2[CH:14]=[C:13]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:12]=[C:11]([C:9]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:10])[N:16]2[CH:2]=1)=[O:22])[CH3:25]
Reactant: C1CCNC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OCC)n2n1
Reactant: c1c[nH]cn1
Product: CCNC(=O)Nc1cn2c(C(=O)N3CCCC3)cc(-c3cccnc3)cc2n1
Temperature: 23 °C

Procedure:
A dry mixture of imidazole (2 g) and 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (which may be produced as described in Example 16, Step 1) (0.160 g, 0.452 mmol) was heated until it became a homogeneous melt. It was then allowed to cool and solidify. To the solid was added pyrrolidine (0.1 mL) and the mixture was heated until it became a homogeneous melt, then allowed to cool to 23° C. Additional pyrrolidine (0.1 mL) was added and the reaction was heated at melt temperature for 30 sec. The reaction was cooled to RT and allowed to solidify. The solid was partitioned between water and EtOAc and the aqueous layer was extracted EtOAc (3×15 mL). The combined organic layers were then washed with brine and dried over sodium sulfate. Evaporation in vacuo gave a solid that was purified by silica gel chromatography (gradient elution 2-30% isopropanol/dichloromethane) to give the desired product. MS (APCI+)=380.1
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:22]([CH3:21])[C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=341.1 [MH+].
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[C:11]([O:14][C@@:15]1([C:35]#[CH:36])[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl.COCOC>[C:11]([O:14][C@@:15]1([C:35]#[CH:36])[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]1)[C:23](=[CH2:1])[CH2:22]3)(=[O:13])[CH3:12]
Reactant: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: COCOC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 60.9 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of chloroform and 30 ml of methylal is combined with 1.9 ml of phosphorus oxychloride and refluxed for 1 hour. The reaction mixture is combined with 1.0 g of 17β-acetoxy-17α-ethynyl-4-androsten-3-one and, under reflux, 1.9 ml of phosphorus oxychloride is added dropwise within 2 hours. The mixture is refluxed for 1 hour, cooled, and rendered alkaline by the dropwise addition of saturated soda solution. The organic phase is separated and concentrated under vacuum. For working-up purposes, the crude product is mixed with a small amount of methylene chloride and water, as well as 5 g of soda. After steam distillation, the product is vacuum-filtered, the residue washed neutral with water, and purified on 105 g of silica gel with a hexane/ethyl acetate gradient (0-50% ethyl acetate). In this way, 630 mg of 17β-acetoxy-17α-ethynyl-6-methylene-4-androsten-3-one is isolated, mp 158°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH2:21]([CH:23]([C:28]1[S:32][C:31]([NH2:33])=[N:30][N:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:22].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:21]([CH:23]([C:28]1[S:32][C:31]([NH:33][C:15](=[O:17])[C@@H:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])=[N:30][N:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:22]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CCCCC(CC)c1nnc(N)s1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)c1nnc(NC(=O)[C@H](CCC)NC2CCc3cc(F)cc(F)c3C2)s1

Procedure:
A mixture of 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (28 mg), 5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-ylamine (20 mg), O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (30 mg), diisopropylethylamine (0.04 ml) in DMF (1 ml) was shaked in shaker overnight. The mixture was quenched with water, basified with satuated sodium bicarbonate, and extracted twice with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to give the crude material. The crude material was purified by biotage silica gel column chromatography using methylene chloride to 3% methanol in methylene chloride to give the title compound as a glass foam. LC-MS RT=2.5 min, M+1=465.0, M−1=463.2. The corresponding HCl salt was prepared as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([CH:24]=[CH:25][N:26]=2)[N:23]=1.O>O1CCCC1.CN(C)C=O>[CH3:27][C:19]1[C:18]([O:16][CH2:15][CH2:14][CH2:13][S:10]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)(=[O:12])=[O:11])=[N:23][N:22]2[CH:24]=[CH:25][N:26]=[C:21]2[CH:20]=1
Reactant: CN1CCN(S(=O)(=O)CCCO)CC1
Reactant: Cc1cc2nccn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2nccn2nc1OCCCS(=O)(=O)N1CCN(C)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In 20 ml of tetrahydrofuran-dimethylformamide (3:1) was suspended 110 mg of60% sodium hydride in oil followed by addition of 611 mg of 3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture was stirred under nitrogen at room temperature for 30 minutes and at 50° C. for30 minutes. Then, 420 mg of 6-chloro-7-methylimidazo[1,2-b]pyridazine was added and the mixture was further stirred at 50° C. for 1 hour and at 70° C. for 1 hour. Following addition of 100 ml of iced water, the reaction mixture was extracted with ethylacetate (100 ml ). The extract was washed with 50 ml of saturated saline and dried over anhydrousmagnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethanemethanol (50:3). The fraction containing the desired product were pooled and concentrated. The residue was recrystallized dichloromethane-isopropyl ether to obtain 447 mg of the title compound.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])[CH:22]=[N:21]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H](O)CO)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (1.21 g, 2.33 mmol) in methanol (23 mL, 0.1 M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (66.3 mg, 0.34 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (200 mL) and was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and then concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 1-10% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.86 g, 77%) as a white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C22H25N5O5F2 [M+H+] 478.1897 found 478.1896. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.8 Hz, 3H) 0.89 (d, J=6.8 Hz, 3H) 1.38-1.51 (m, 1H) 1.80 (ddd, J=13.6, 9.4, 4.3 Hz, 1H) 2.10-2.26 (m, 1H) 3.21-3.51 (m, 2H) 3.71-3.81 (m, 1H) 3.82-3.92 (m, 1H) 4.09 (dd, J=13.6, 3.9 Hz, 1H) 4.70 (t, J=5.6 Hz, 1H) 4.91-4.96 (m, 1H) 5.52 (dd, J=11.0, 3.9 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: C([Sn](=O)CCCC)CCC.C[Si]([N:15]=[N+:16]=[N-:17])(C)C.C[C:19]1[C:20]([CH:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)[CH:34]=[CH2:35])=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]=2[CH:28]=1.CC1(C)CCC(C)(C)C2C=C(C(C3C=CC(C#N)=CC=3)C=C)C=CC1=2>C1(C)C=CC=CC=1>[CH3:29][C:26]1([CH3:30])[CH2:25][CH2:24][C:23]([CH3:31])([CH3:32])[C:22]2[CH:21]=[C:20]([CH:33]([C:36]3[CH:43]=[CH:42][C:39]([C:40]4[NH:41][N:17]=[N:16][N:15]=4)=[CH:38][CH:37]=3)[CH:34]=[CH2:35])[CH:19]=[CH:28][C:27]1=2
Reactant: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C=CC(c1ccc(C#N)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: C=CC(c1ccc(-c2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 110 °C
Yield: 73 %

Procedure:
Dibutyl tin oxide (75 mg, 10% mol) and trimethylsilyl azide (0.97 ml, 7.28 mmol), are added successively to a solution of the (Z) compound 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzonitrile (1.20 g, 3.64 mmol) in anhydrous toluene (6.25 ml). The reaction medium is heated for 16 hours at reflux (110° C.) under an atmosphere of argon and with magnetic stirring. The mixture is purified by flash chromatography on silica (eluent CH2Cl2 then MeOH:CH2Cl2=5:95) to obtain, after evaporation, washing with hexane and drying at the palette pump, 0.99 g of a white powder, the compound (Z) 5-[4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]phenyl]-1H-tetrazole (compound CB92834) (yield=73%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:14]2[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]3[CH:10]=[C:9]([CH3:28])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:12]=3[CH:13]=2)[CH2:23][CH2:24]1)(=[O:31])[CH3:30]
Reactant: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.25 h

Procedure:
To 6-benzyl-1,7-dimethyl-N-piperidin-4-yl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (10. mg, 0.027 mmol, from Example 206) in DCM (1.0 mL) was added acetyl chloride (2.3 μL, 0.032 mmol, Aldrich), followed by the addition of triethylamine (7.4 μL, 0.053 mmol). After 15 minutes, volatiles were removed in vacuo. The mixture was diluted with water and MeOH, and the product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (7.6 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:66])[C@H:56]([NH:64][CH3:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:49])[CH3:48]>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:66])[C@H:56]([N:64]([C:11](=[O:13])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:65])[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)(=[O:49])[CH3:48]
Reactant: CN[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionic acid (659 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (3 mL) and dichloromethane (3 mL). The solution was cooled to 0° C. 1-Hydroxy-7-azabenzotriazole (272 mg, 2.0 mmol) was added. After 10 min N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) was added. The reaction mixture was stirred for 10 min. A solution of 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propyl acetate (567 mg, 2.0 mmol) in dichloromethane (4 mL) was added. The solution was stirred for 16 hours, while the temperature rose to room temperature. The reaction mixture was diluted with ethyl acetate (150 mL). It was extracted with 10% sodium hydrogensulfate solution (150 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) and the organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g) with ethyl acetate/heptane (2:1) to give 973 mg of 3-((2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(O)(=O)C>O>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Reactant: CCOC=C(C#N)C#N
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A solution of 15 g of 2,3,4-trichlorophenylhydrazine, 8.7 g of (ethoxymethylene)malononitrile, 100 ml of glacial acetic acid and 50 ml of water was refluxed for 3 hours. The reaction mixture was cooled, poured into ice water and the precipitated solid was collected by filtration and dried. This solid was dissolved in ethyl acetate and the resulting solution was washed twice with saturated sodium bicarbonate, once with 100 ml of water, once with 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was recrystallized from ethanol to give 13.2 g of 5-amino-1-(2,3,4-trichlorophenyl)-1H-pyrazole-4-carbonitrile. Yield 66%. mp=140°-142° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]1=2>[Pd].O1CCCC1>[NH2:9][C:3]1[C:2]([CH3:1])=[CH:7][N:6]([CH:18]2[CH2:19][CH:15]([OH:14])[CH:16]=[CH:17]2)[C:5](=[O:8])[N:4]=1
Reactant: Cc1c[nH]c(=O)nc1N
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1N
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
50 g (0.4 mol) of 5-methylcytosine are added to a solution of the palladium(0) catalyst (1.6 mol %) prepared in situ as described above in 200 ml of dry tetrahydrofuran/200 ml of dry dimethylsulfoxide at 5° C. 49.2 g (0.6 mol) of epoxycyclopentene, dissolved in 100 ml of tetrahydrofuran, are added dropwise to this suspension, while stirring (1.5 hours). The mixture is stirred at room temperature for 3 days and then concentrated, and the residue is stirred with 2N sodium carbonate solution, filtered off and washed with water and acetone. 20.2 g (24.4% of theory) of 4-amino-5-methyl-1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]pyrimidin-2(1H)-one of melting point 241°-245° C. are obtained. Chromatography (silica gel, methylene chloride/methanol 3/1) of the neutralized mother liquor gives, in addition to 5-methylcytosine (14.95 g, melting point 264°-269° C.) a further 9.87 g (11.9% of theory) of the title compound; total yield: 36.3% of theory. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.23 (s, 1H), 7.12 (s, broad, 1H), 6.70 (s, broad, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:13]
Reactant: OC1CCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of cyclobutanol (720 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 140° C. to give 1.00 g of the product 469. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.03 (m, 1H), 3.98 (s, 2H), 2.28-2.15 (m, 2H), 2.08-1.95 (m, 2H), 1.7 (q, 1H), 1.50 (m, 1H), 1.28 (t, 3H)
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH2:10])=[N:4][N:3]=1.C([O-])(O)=O.[Na+].O=C1CCC(=O)N1[O:23][C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1)=O.C1COCC1.CC#N>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:24]([C@H:26]2[CH2:27][CH2:28][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]2)=[O:23])=[N:4][N:3]=1
Reactant: NCc1nnc(N)[nH]c1=O
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-(aminomethyl)-1,2,4-triazin-5(4H)-one [J. Heterocyclic Chem., (1984), 21 (3), 697] (2.00 g, 0.0113 mol) in H2O (60.0 mL, 3.33 mol) was cooled to 0° C. and drop wise charged with 1.00 M of NaHCO3 in H2O (22.5 mL) and allowed to warm to rt. This mixture was charged with methyl trans-4-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}cyclohexanecarboxylate (3.8 g, 0.012 mol) in 1:1 THF/MeCN (40 mL). After 30 min a precipitate began to form in the reaction. This was allowed to stir at rt for an additional 16 h and was filtered through a fritted funnel and washed with H2O (2×), diethyl ether (2×), and dried in vacuo resulting in the title compound 2.92 g, (84% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.55 (m, 4H), 1.83 (s, 2H), 1.98 (d, J=10.61 Hz, 2H), 2.27 (s, 2H), 3.64 (s, 3H), 4.10 (d, J=5.81 Hz, 21H), 6.81 (br. s., 2H), 7.91 (t, J=5.56 Hz, 1H) and 11.98 (br. s., 1H); MS (ES+): m/z 310.05 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1

Procedure:
To a solution of 1.3 g (3.03 mmol) of 2-{2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethyl}-isoindole-1,3-dione, prepared in step 1.3. in 30 mL of ethanol is added slowly at room temperature 0.485 g (15.13 mmol) of hydrazine monohydrate. The reaction mixture is then refluxed for 3 hours.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[BrH:12].[Br:13][CH2:14][CH2:15][CH2:16][NH2:17]>ClC1C=CC=CC=1Cl.CO>[Br-:13].[NH3+:17][CH2:16][CH2:15][CH2:14][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Br-:12]
Reactant: Cc1ccnc2ccccc12
Reactant: Br
Reactant: NCCCBr
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: Cc1cc[n+](CCC[NH3+])c2ccccc12
Product: [Br-]
Temperature: 135 °C
Yield: 18.4 %

Procedure:
A mixture of lepidine (3.0 g, 21 mmol) and 3-bromopropylamine hydrobromide (4.6 g, 21 mmol) in 1,2-dichlorobenzene (50 mL) was heated at 135° C. for 16 hours. The mixture was cooled and 1,2-dichlorobenzene was decanted. The residue thus obtained was suspended in methanol (25 mL) and refluxed for 10 min. It was cooled and separated solid was collected by centrifugation, washed with methanol (2×30 mL) and dried under high vacuum to yield Compound 2 as an light gray solid (1.4 g, 19%). This product was used without further purification. The structure of Compound 1 is given below: