Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O>>[CH3:1][CH:2]1[S:6][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[S:5][CH:3]1[CH3:4]
Reactant: CC(S)C(C)S
Reactant: O=C1CCCCC1Cl
Product: CC1SC2=C(CCCC2)SC1C
Yield: 49 %

Procedure:
The procedure of Example 1(a) is followed using 2,3-butanedithiol and 2-chlorocyclohexanone to give 5,6,7,8-tetrahydro-2,3-dimethyl-1,4-benzodithian as a greenish oil, b.p. 90°-100°/0.07 mm. Yield 49%. NMR 1.34 (6d), 1.45-2.25 (8m), 2.7-3.1 (2m). IR 2900, 1610, 1435, 1365, 1320, 1115, 795, 690.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:9][C:8]=1[CH3:18])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][C:8]=1[CH3:18])[C:15](=[O:17])[CH2:14][CH2:13]2)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)O)ccc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN(CC(=O)OCC)c1cc2c(cc1C)C(=O)CC2
Temperature: 40 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
To dichloromethane (68 ml) were added the compound (4.79 g, 13.6 mmol) obtained in step C, N,N-dimethylformamide (5 drops) and oxalyl chloride (2.59 g, 20.4 mmol), and the mixture was stirred at 40° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloroethane (68 ml) and cooled in an ice water bath. To this solution was added aluminum chloride (2.54 g, 19.0 mmol) by small portions, and the mixture was stirred at 90° C. for 4 hr. The reaction mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.59 g, yield 57%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].CC[O-].[Na+].[Na].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[O:3]=[C:2]1[NH:4][C:13](=[O:12])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:1]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 23.1 %

Procedure:
Urea (12 g, 200 mmol) was added to EtOH (300 mL) containing NaOC2H5 previously prepared from sodium (5.52 g, 240 mmol, 1.2 eq). Diethyl 2-(ethoxymethylene)malonate (43.2 g, 200 mmol, 1.0 eq) was added and the solution was stirred at 20° C. for 24 h, and then stirred at 90° C. for 24 h. The alcohol was removed by reduced pressure distillation. Ice-water (100 mL) was added to dissolve the residue. The product was precipitated by adding cold dilute hydrochloric acid. The solid was filtered off to afford ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (8.5 g, 23%), which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][C:31](O)=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:30][C:31]([NH2:39])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC(=O)O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(CC(N)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of racemic 3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 163a, (0.50 g, 0.94 mmol) in 15 mL of THF was added HBTU (0.36 g, 0.95 mmol). The reaction was stirred for 15 minutes and then ammonia gas was bubbled through for 5 minutes. The reaction was allowed to stir for 12 hours and then concentrated to dryness. The residue was redissolved in 20 mL of MeOH and treated with 3 mL of 2N LiOH. The reaction was warmed to 60° C. for 3 hours and then concentrated to dryness. The residue was purified by silica gel chromatography (EtOAc) to afford 250 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.78 minutes (M+H) 375.45.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][CH:18]=[C:19]([CH2:21]O)[N:20]=3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][C:19]1[N:20]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[O:17][CH:18]=1
Reactant: OCc1coc(-c2ccc(-n3cnc4ccccc43)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1coc(-c2ccc(-n3cnc4ccccc43)cc2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of {2-[4-(1H-benzimidazol-1-yl)phenyl]-1,3-oxazol-4-yl}methanol (0.35 g, 1.2 mmol) in CH2Cl2 was cooled to 0° C., treated with a solution of thionyl chloride (0.37 g, 3.0 mmol) in CH2Cl2, stirred at 0° C. for 3 h and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed sequentially with water and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure to afford the title product, 1HNMR (CDCl3, 400 MHz): 8.25 (d, J=8.4 Hz, 2H), 8.17 (s, 2H), 7.67 (d, J=8.0 Hz, 1H), 7.60 (d, J=5.6 Hz, 1H), 7.36-7.38 (m, 3H), 7.26 (s, 1H), 4.61 (s, 2H). LCMS (ESI+) 310 (MH+).
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[CH2:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[CH3:30].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:29]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]3=[O:28])[CH2:6][CH2:5]2)=[CH:33][CH:32]=1)[CH3:30]
Reactant: CCc1ccc(C=O)cc1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cc(C(=O)NC)c4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 82.1 %

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 48 mg of 4-ethylbenzaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 0.14 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[CH:12])=[CH:8][CH:9]=2)[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:8][CH:9]=2)[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)C(C)C2(C)C
Product: CC1C(C)(C)c2ccc(C#Cc3ccc(C=O)cc3)cc2C1(C)C
Yield: 29.1 %

Procedure:
Using a procedure similar to that described in Example 1c, 8 g (40 millimoles) of (2,3-dihydro-1,1,2,3,3-pentamethyl-5(1H)-indenyl)-ethyne and 4.6 g (25 millimoles) of 4-bromobenzaldehyde were reacted, the solution was filtered and the filtrate was evaporated down to give a residue, which was extracted with sodium bicarbonate solution/methylene chloride. Stirring the residue with methylene chloride and a little cyclohexane gave 2.3 g (29%) of the title compound of melting point 106°-107° C.
Reaction SMILES: [C:1]([C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Br:10]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:10][CH2:2][C:1]([C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1snnc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnsc1C(=O)CBr
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 5-acetyl-4-methyl-1,2,3-thiadiazole (1.00 g, 7.03 mmol) in chloroform (20 ml) was added dropwise a solution of bromine (1.24 g, 7.73 mmol) in chloroform (10 ml) over 0.5 h at room temperature. The mixture was heated at reflux temperature for 2 h. After cooling to room temperature, the mixture was made basic with saturated aqueous sodium bicarbonate and extracted with dichloromethane (100 ml×2). The extracts were dried (Na2SO4) and concentrated to give 1.55 g (100%) of the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](Cl)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc(N)cc2)C3=O)CC1
Yield: 72.7 %

Procedure:
A mixture of 3-(4-amino-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.1 g, 0.30 mmol) and 1-methylpiperazine (36 mL, 0.36 mmol) in dry pyridine (5.0 mL) was heated at reflux temperature overnight. After evaporation of the solvent in vacuo, the residue was diluted with water (50 mL), and resulting suspension was extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL×2) and dried over anhydrous MgSO4 concentrated under reduced pressure. The pure objective compound (87 mg, 73%) was obtained as yellow solid by a flash column chromatography (CH2Cl2:MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.78 (s, 3H, CH3) 2.35 (s, 3H, NCH3), 2.43-2.67 (m, 4H, NCH2), 2.90-2.95 (m, 4H, NCH2), 3.67 (br s, 2H, NH2), 6.38 (d, J=1.8 Hz, 1H, ArH), 6.54-6.61 (m, 3H, ArH), 7.04 (d, J=8.6 Hz, 2H, ArH), 8.44 (br s, 1H, NH).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[K].[CH2:20]([NH:27][S:28](=[O:31])(=[O:30])[NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][S:28](=[O:30])(=[O:31])[NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[Cl:17]
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Reactant: NS(=O)(=O)NCc1ccccc1
Agent: [K]
Product: COc1ccc(Cl)c(Oc2c(Cl)ncnc2NS(=O)(=O)NCc2ccccc2)c1
Yield: 47 %

Procedure:
Benzylsulfamic acid [6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide (0.7 g) was prepared from 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine (1 g) and benzylsulfamic acid amide potassium salt (1.21 g) according to the procedure described in Referential Example 15. LC-MS: tR=5.13; [M+H]+=456.91.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[CH:14])([CH3:4])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CC(C)=O.C([O-])(=O)C.[Ag+]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[C:14][Cl:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C#CCOc1ccccc1C(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1OCC#CCl
Yield: 102.4 %

Procedure:
To a solution of Example 100A (22.2 g, 118 mmol) in acetone (300 mL) was added N-chlorosuccinimide (18.8 g, 141 mmol) and silver acetate (1.96 g, 11.7 mmol). The reaction was heated to reflux for 24 h, cooled, and the solvent removed by evaporation. The residue was taken up in a mixture of water (125 mL) and diethyl ether (125 mL), and filtered to remove the undissolved silver salts. The filtrate was extracted with diethyl ether (150 mL), and the combined organic layers washed with brine (75 mL) and concentrated to produce 26.9 g of the crude title compound which was used without further purification. MS (DCI/NH3) m/z 240 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[CH2:8]2.[N+:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:15])([O-:18])=[O:17]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc2c(c1OC)CCC(=O)C2
Product: COc1cc(C=C2C(=O)CCc3c2ccc(OC)c3OC)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 5,6-dimethoxy-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 70-72° C.; IR (Nujol): 1715, 1550; 1H NMR: δ2.59 (2H, t), 3.06 (2H, t), 3.78 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 6.47 (1H, s), 6.77 (1H, d, J=8.2), 7.41 (1H, d, J=8.2), 7.67 (1H, s); 13C NMR: δ19.7, 32.0, 56.3, 56.7, 56.8, 56.85, 108.1, 121.9, 125.6, 126.1, 128.0, 129.2, 132.1, 132.9, 133.7, 140.3, 141.4, 149.3, 152.9, 153.5, 200.9; Anal. (C21H21NO7) C, H, N.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:15]=[C:14]([S:28][CH3:29])[N:13]=1>O1CCCC1>[CH2:3]([O:10][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:15]=[C:14]([S:28][CH3:29])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of sodium hydride (630 mg, 60% dispersion in mineral oil) in tetrahydrofuran (20 ml) at 0° C. was added benzyl alcohol (1.09 ml). The mixture was stirred for 15 minutes then a solution of 4-chloro-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (1.6 g) in tetrahydrofuran (14 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for two hours. Solvent was evaporated under reduced pressure and the remaining residue dissolved in dichloromethane (200 ml) and washed with water (2×150 ml). Organics were separated, dried over sodium sulphate and solvent was removed under reduced pressure to yield crude product (2.5 g). Flash chromatography on silica yielded product 4-benzyloxy-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (1.75 g) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C(=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Fc1cc(I)ccn1
Solvent: CC(=O)N(C)C
Product: Ic1ccnc(NCCCN2CCOCC2)c1

Procedure:
A solution of 4-iodo-2-fluoropyridine (2.32 g, 10.00 mmol) and N-(3-aminopropyl)morpholine (4.2 ml, 26.00 mmol) in N,N-dimethylacetamide (30 ml) was heated to 100° C. for 20 hours before being concentrated in vacuo, to afford the crude title compound which was used without any further purification; Mass Spectrum: M+H+ 348.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=CC=CC=1[Cl:28]>>[Cl:28][C:17]1[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=1[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Reactant: Clc1ccccc1CBr
Product: COc1cc(SCc2ccccc2Cl)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-2-chlorobenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>[Ni](Cl)Cl.C(OCC)C>[CH2:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: Clc1ccccc1Cl
Agent: Cl[Ni]Cl
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccccc1CCCCCCCCCCCC
Temperature: 0 °C
Yield: 84 %

Procedure:
To a 200 ml Schlenk reaction vessel were added under a nitrogen atmosphere 2.7 ml (24.0 mmol) of 1,2-dichlorobenzene, 66 mg (0.12 mmol) of nickel chloride {bis(diphenylphosphino)propane}, and 18 ml of diethyl ether. The whole was cooled to 0° C. and 65 ml (65 mmol) of a diethyl ether solution of n-dodecylmagnesium bromide (manufactured by Sigma-Aldrich, 1.0M) was added dropwise. After 11 hours of the reaction at 35° C., the reaction was stopped by adding 3N hydrochloric acid. The mixture was extracted with diethyl ether and the organic phase was washed with water and a saturated aqueous sodium hydrogen carbonate solution. The phase was dried over calcium chloride and the solvent was concentrated under reduced pressure. The residue was dried under vacuum (20 Pa) at 170° C. to obtain a liquid of 1,2-didodecylbenzene (8.36 g, yield 84%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH2:18]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]>>[CH2:18]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]([N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][C:7]3[NH:8][C:9](=[O:17])[C:10]4[CH2:16][O:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: CC#CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: CC#CCOc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Yield: 28.6 %

Procedure:
The title compound (90 mg) was prepared following the general procedure of Example 1 from 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (140 mg, 0.59 mmol) and [4-(4-but-2-ynyloxy-benzoyl)-piperidin-1-yl]-acetic acid (187 mg, 0.59 mmol). 1H NMR (400 MHz, MeOD) δ: 8.01 (d, J=8.6 Hz, 2H), 7.08 (d, J=9.1 Hz, 2H), 4.79-4.76 (m, 2H), 4.66 (s, 1H), 4.57 (s, 1H), 4.50-4.45 (m, 2H), 4.39 (s, 2H), 3.92 (t, J=5.6 Hz, 2H), 3.80-3.67 (m, 2H), 3.36 (d, J=7.1 Hz, 2H), 3.33-3.28 (m, 6H), 2.69-2.58 (m, 2H), 2.22-2.02 (m, 4H), 1.83 (t, J=2.5 Hz, 3H), 1.11-0.89 (m, 1H), 0.66-0.43 (m, 2H), 0.34-0.19 (m, 2H). HRMS calculated for C33H38N4O3=533.2764. found (ESI, [M+H]+), 533.2788. LRMS m/z: ES+=533.7 (M+H), retention time 1.08.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.C(OCC)C.[Pd]>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:33]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[NH:34])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4cccs4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (150 mg, 0.378 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon, (40.3 mg, 0.0378 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) showed complete conversion to 8a 1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (10 mL) and the ethanolic solution of the amine 8a is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (140 mg, 0.491 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 67 hours. The solution was diluted with diethyl ether (80 ml) and cooled in and ice bath resulting in the formation of an off-white precipitate that was collected on a sintered glass funnel and washed with ether. The hygroscopic solid was solubilized on the funnel in methanol and the solvent collected and evaporated to yield crude solid. The solid was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 8. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford yellow residue 10 N-[1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzo-imidazol-5-yl]-thiophene-2-carboxamidine. Yield: 94 mg (52.2%). 1H NMR (DMSO) δ: 0.82 (t, 6H, J=7.1), 1.29 (t, 3H, J=7.0), 2.45 (q, 4H, J=7.0), 2.45-2.50 (m, 2H), 3.98 (q, 2H, J=7.0), 4.07-4.13 (m, 2H), 4.22 (s, 2H), 6.31 (br s, 2H), 6.72 (d, 1H, J=7.7), 6.88 (d, 2H, J=8.7), 6.99 (s, 1H), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.4), 7.35 (d, 1H, J=8.4), 7.59 (d, 1H, J=5.1), 7.72 (d, 1H, J=3.4); MS (ESI): 476 (MH+, 100%)