Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C:4]([CH3:16])([CH3:15])[C:3](=[O:17])[CH2:2][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)=[CH:9][CH:10]=1
Reactant: CC(C)(CCOc1ccc(Cl)cc1)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCOc1ccc(Cl)cc1)C(=O)Cn1cncn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
A solution of 55 g (0.2 mol) of 1-chloro-5-(4-chlorophenoxy)-3,3-dimethyl-2-pentanone in 50 ml of acetone is added dropwise to a mixture of 27.6 g (0.2 mol) of potassium carbonate and 27.6 g (0.4 mol) of 1,2,4-triazole in 400 ml of boiling acetone. The mixture is boiled for a further 3 hours, cooled down to 20° C., filtered and the filtrate is evaporated in vacuo. The oily residue is taken up in 250 ml of ethyl acetate and washed three times with 100 ml of water each time. After drying the organic phase over anhydrous sodium sulphate, it is evaporated in vacupo. the residual crude product (61 g) is dissolved in 250 ml of acetone, and a solution of 57.6 g of naphthalene-1,5-disulphonic acid in 250 ml of acetone is added. The salt which has crystallized out (45.4 g; melting point 188°-190° C.) is suspended in a mixture of 150 ml each of dichloromethane and water and is made alkaline by the addition of 10% strength sodium carbonate solution. The organic phase is separated off, and the aqueous phase is extracted once more with 100 ml of dichloromethane and the combined organic phases are evaporated in vacuo. 30.4 g (49.4% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-pentanone are obtained as a pale yellowish liquid of refractive index nD20 =1.5457.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18][C:20]#[N:21])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1cn2cccc(OCc3ccccc3)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
A mixture of 1.79 g 8-benzyloxy-2-chloromethylimidazo[1,2-a]pyridine, 0.90 g sodium cyanide, and 15 ml dimethylformamide was heated on a steam bath for 1.5 hr. The mixture was cooled and evaporated in vacuo, the residue was taken up in chloroform (50 ml) and filtered through a pad of silica gel, the filtrate was evaporated in vacuo, and the residue recrystallized from acetonitrile to give the title compound (m.p. 148°-150°C.).
Reaction SMILES: [F:1][C:2]([F:24])([O:7][C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[O:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][CH2:15][CH2:16]Cl)[C:3]([F:6])([F:5])[F:4].FC(F)(OC(F)(F)C(F)(F)OC(F)(F)COCCCBr)C(F)(F)F.[CH2:49]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH2:49]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:21])([F:20])[C:8]([F:23])([F:22])[O:7][C:2]([F:24])([F:1])[C:3]([F:6])([F:5])[F:4])([F:19])[F:18])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Agent: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining a mixture of 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride and 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl bromide (75:25 mole ratio, total 4.18 g, 10 mmol, Example 20) with 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine (3.18 g, 10.0 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation (240° C. at 0.4 torr) to provide a yield of 4.3 g.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, methyl 2-bromopropanoate (1.5 eq) and Cs2CO3 (1.5 eq): MS (ES) m/z 311 (M+1).
Reaction SMILES: CC([O:4][C:5]([C:7]1[N:39]=[CH:38][C:10]2[N:11]([CH2:26][C:27]([N:29]([CH3:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:40][O:41][CH3:42])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])C.[OH-].[Na+].Cl>CO>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]1[C:8]([CH2:40][O:41][CH3:42])=[C:7]([C:5]([OH:6])=[O:4])[N:39]=[CH:38][C:10]=1[N:11]2[CH2:26][C:27]([N:29]([CH3:37])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1c(C(=O)O)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)Cc1ccccc1
Yield: 86.9 %

Procedure:
460 mg of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-benzyl-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is mixed in 3 ml of methanol with 1 ml of aqueous 2N sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, the precipitated reaction product is suctioned off, washed with water and diethyl ether and dried in a vacuum. 370 mg of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-benzyl-amino]-2-oxoethyl}-9H-pyrido-[3,4-b]indole-3-carboxylic acid (decomposition starting at 239°) is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12](C(C)=C)[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.[O-][Mn](=O)(=O)=O.[K+].[OH-].[Na+]>CC(O)(C)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[NH:12][C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1
Reactant: C=C(C)n1c(OCCCCCBr)nc2ccccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: BrCCCCCOc1nc2ccccc2[nH]1
Yield: 42.8 %

Procedure:
1.2 g of the compound obtained in Example 13b was dissolved in 10 ml of tBuOH, slowly added dropwise with 30 ml of a mixed solution of KMnO4; (1.92 g) and 50 ml of 0.1 N NaOH, and stirred for 1 hour. The reaction mixture was extracted three times with chloroform. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.45 g of the title compound (yield: 43%).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH:14]=[O:15])[CH:8]=1)C.[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[CH:14]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[CH:10]=1)[O:6][CH2:5][C:4]([OH:16])=[O:3])=[O:15]
Reactant: CCOC(=O)COc1cc(C)cc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C=O)cc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-(3-formyl-5-methyl-phenoxy)-acetic acid ethyl ester (0.79 g) in methanol (4 ml) at 5° C. was treated with a 2M sodium hydroxide solution (3.6 ml). After 15 min the mixture was allowed to warm to room temperature. After a further 2 h the stirred solution was again cooled to 5° C. and covered with ethyl acetate and the aqueous layer was adjusted to acidic pH with 2M hydrochloric acid. The layers were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic phase was washed with water and brine and dried with magnesium sulphate. Concentration gave a gummy solid which was triturated with diethyl ether giving, after drying, the title compound (0.47 g) as a pale yellow solid. Hplc system 1 (λ=254 nm) Rt 5.2 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([NH2:29])[CH:25]=[CH:26]2)=[N:21]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(=O)(O)[O-].[Na+].CC(C)=O.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:29][C:24]2[CH:25]=[CH:26][C:27]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:19])[CH:28]=3)=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc2ccc(N)cc2n1
Reactant: O=C(O)c1ccccc1NCc1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Yield: 95.8 %

Procedure:
0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid, 0.471 g (3.2 mmol) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68 mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) in 25 ml of dimethylformamide are stirred for 16 hours at room temperature. The dimethylformamide is drawn-off in an oil pump vacuum. The remaining residue is drawn off in saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The residue is chromatographed on silica get with a gradient that consists of hexane:acetone=100:0 to 50:50 as an eluant. 0.669 g (96% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide is obtained in the form of a beige foam.
Reaction SMILES: [C:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[N:9][C:10]=2[C:15]([O-])=[O:16])([CH3:4])([CH3:3])[CH3:2].[NH2:25]C1C(C([O-])=O)=NC(C2C=CC=C(O)C=2)=NC=1NC(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>>[C:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[N:9][C:10]=2[C:15]([NH2:25])=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1c(=O)[nH]c2c(C(=O)[O-])nc(-c3cccc(O)c3)nc21
Reactant: CC(C)(C)Nc1nc(-c2cccc(O)c2)nc(C(=O)[O-])c1N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)n1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 46 %

Procedure:
9-tert-Butyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. 5-Amino-6-tert-butylamino-2-(3-hydroxy-phenyl)-pyrimidine-4-carboxylate (0.26 g, 0.79 mmol) and 1,1′-carbonyldiimidazole (0.64 g, 4.0 mmol) were reacted according to General Procedure F. The crude residue was purified using Biotage silica gel chromatography (0-50% ethyl acetate in hexanes) to afford the title compound (0.13 g, 0.36 mmol, 46% yield). MS (ESI) m/z 357.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cccc(Oc2ccc(-c3ccccc3)cc2CN2CCOC2=O)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 29.9 %

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.1 g, 0.24 mmol), phenylboronic acid (0.044 g, 0.36 mmol), tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.02 mmol), and potassium carbonate (0.082 g, 0.59 mmol) were combined in DME:H2O (2:1; 3 mL) and stirred at 90° C. for 5 hours. Once no starting material was seen by analytical LCMS, the pH was adjusted to pH 7 with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography to give the desired product (0.03 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]1([C:27]#[C:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]=2[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: FC(F)(F)c1cc(Br)c2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)n1cnc2c(Br)cc(C(F)(F)F)cc21
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-6-trifluoromethylbenzimidazole (1.00 g, 3.77 mmol) in DMF (10 mL) was added potassium carbonate (520 mg, 3.77 mmol) and ethyl phenylpropiolate (690 μL, 4.15 mmol). The suspension was then warmed to 100° C. for 4 hours, cooled to room temperature, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99:1), to afford the title compound as a mixture of geometric isomers (ca. 6:1 as determined by 1H NMR). 1H NMR: (CDCl3) of the mixture, 8.16 (s), 8.13 (s), 7.76 (br), 7.57-7.17 (m), 6.61 (s), 6.30 (s), 4.18 (q, J=7.32), 4.07 (q, J=7.32), 1.21 (t, J=7.32), 1.10 (t, J=7.32).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]([NH2:20])=[O:19])[S:16][CH:17]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([C:18]([NH2:20])=[O:19])[S:16][CH:17]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2csc(C(N)=O)n2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1nc(-c2ccc(O)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Boron tribromide (3.7 ml) was added dropwise under nitrogen to a suspension of 4-(4-methoxyphenyl)-thiazole-2-carboxamide (3 g) in dichloromethane (45 ml). The mixture was stirred at room temperature for 2 h, then under reflux for 2 h and then cooled, after which water (60 ml) was added cautiously. The precipitate was filtered and the collected solid was dried under vacuum at 50° C., and recrystallised from methanol to give 4-(4-hydroxyphenyl)-thiazole-2-carboxamide (2.03 g), m.p. 223°-227° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([CH:12]2[CH2:14][CH2:13]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)c(Cl)nc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C2CC2)c(Cl)nc1Cl
Yield: 70.3 %

Procedure:
A mixture of compound 2,6-dichloro-5-iodonicotinonitrile (10 g, 33.4 mmol), cyclopropylboronic acid (3.5 g, 40.1 mmol), K3PO4 (28 g, 133.6 mmol), Cy3P (1 g, 3.3 mmol) and Pd(OAc)2 (0.5 g, 2.2 mmol) in Toluene/H2O (300 mL/15 mL) was stirred under refluxing overnight. The mixture was poured into water and extracted with EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1) to give compound 2,6-dichloro-5-cyclopropylnicotinonitrile (5 g, 70%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.43 (s, 1H), 2.08 (m, 1H), 1.18 (m, 2H), 0.69 (m, 2H)
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=O)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([NH2:69])[CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]2[NH:69][C:64]3[CH:63]=[N:62][CH:67]=[CH:66][C:65]=3[N:68]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccncc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nc2ccncc2[nH]1
Reaction time: 0.17 h

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (400 mg, 1.172 mmol) in DMF (5 mL) were added BOP (580 mg, 1.289 mmol) and DIPEA (0.246 mL, 1.406 mmol) at room temperature. After being stirred for 10 minutes, pyridine-3,4-diamine (130 mg, 1.230 mmol) was added and stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (10% MeOH in DCM/DCM). The obtained residue was stirred in acetic acid (5 mL) for 4 hours. The reaction mixture was concentrated and purified by silica gel flash column chromatography to give (S)-tert-butyl 2-(biphenyl-4-yl)-1-(3H-imidazo[4,5-c]pyridin-2-yl)ethylcarbamate; 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.33-3.56 (m, 2H), 5.18-5.27 (m, 1H), 5.37-5.48 (m, 1H), 7.22-7.29 (m, 2H), 7.30-7.36 (m, 1H), 7.42 (t, J=7.83 Hz, 2H), 7.48-7.58 (m, 4H), 7.60-7.66 (m, 1H), 8.32 (d, J=5.81 Hz, 1H), 8.94 (s, 1H); MS: m/z (MH+) 415.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(Cl)cc4Cl)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccc(Cl)cc4Cl)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2,4-dichlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([N:19]1[CH2:24][CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO>C1COCC1.[Cl-].[NH4+].C(O)C>[CH2:12]([N:19]1[CH2:20][CH2:21][C@@H:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C@H:23]([OH:9])[CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30% hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69% yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[C:8]#[N:9])[CH2:3][CH2:2]1>CCO.[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:4][CH:1]1[CH2:2][CH2:3]1
Reactant: N#Cc1ccc([N+](=O)[O-])c(NC2CC2)c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N)c(NC2CC2)c1

Procedure:
To a stirred solution of 3-(cyclopropylamino)-4-nitrobenzonitrile (2.0 g, 0.009 mol) in EtOH (20 ml) was hydrogenated using Pd/C for 2 h at room temperature. The reaction was filtered through CELITE® and the filter bed was thoroughly washed with EtOH. The resulting solution was concentrated to provide 4-amino-3-(cyclopropylamino) benzonitrile as a brownish solid. 1H NMR (400 MHz, DMSO-d6), δ: 6.92 (bs, 1H), 6.88-6.86 (d, J=8 Hz, 1H), 6.55-6.53 (d, J=8.4 Hz, 1H), 5.50 (bs, 1H), 5.44 (s, 2H), 2.36-2.34 (m, 1H), 0.76-0.71 (m, 2H), 0.39-0.34 (m, 2H). MS (M+1): 174.
Reaction SMILES: O=C1O[N:5]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:19][CH:18]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)[O:17][C:16]3=[O:32])[CH2:9][CH2:8]2)[NH:3]1.N1(CCC(OC)=O)CCNCC1.O=C1ON=C(N2CCN(CCN3CC(CS(C)(=O)=O)OC3=O)CC2)N1.C(OCC)(=O)C>CO>[C:4]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:26]3)[O:17][C:16]2=[O:32])[CH2:11][CH2:12]1)(=[NH:3])[NH2:5]
Reactant: O=C(O)CCN1CCN(CC2CN(CCN3CCN(c4noc(=O)[nH]4)CC3)C(=O)O2)CC1
Agent: COC(=O)CCN1CCNCC1
Agent: CS(=O)(=O)CC1CN(CCN2CCN(c3noc(=O)[nH]3)CC2)C(=O)O1
Solvent: CO
Solvent: CCOC(C)=O
Product: N=C(N)N1CCN(CCN2CC(CN3CCN(CCC(=O)O)CC3)OC2=O)CC1

Procedure:
1.13 g of 3-[2-(1-(5-oxo-1,2,4-oxadiazolin-3-yl)-4-piperazinyl)ethyl]-5-[4-(2-carboxyethyl)piperazino]methyloxazolidin-2-one [obtainable according to Ex. 1 by reaction of methyl 3-piperazinopropanoate with 3-[2-(1-(5-oxo-1,2,4-oxadiazolin-3-yl)-4-piperazinyl)ethyl]-5-methanesulfonylmethyloxazolidin-2-one and subsequent hydrolysis of the product] are dissolved in 50 ml of methanol and hydrogenated on Raney Nickel. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate in the presence of heat and filtered off with suction after cooling. 3-[2-(1-Amidino-4-piperazinyl)ethyl]-5-[4-(2-carboxyethyl)piperazino]methyloxazolidin-2-one is obtained.