Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:35][C:34]1[CH:33]=[C:32]([C:30]#[C:31][C:2]2[C:3]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(N2CCOCC2)c(Br)cc1NC(=O)OC(C)(C)C
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)c(C#Cc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 20.4 %

Procedure:
tert-Butyl (5-bromo-2-methyl-4-morpholin-4-ylphenyl)carbamate (110 mg, 0.3 mmol), copper(I) iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) were stirred in tetrahydrofuran (0.5 mL) and triethylamine (50 μL, 0.4 mmol) was added. 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was heated to 80° C. for 1 hour. The mixture was filtered through celite and purified by preparative LCMS (pH 2). The product fractions were neutralized with saturated sodium bicarbonate solution, evaporated to remove acetonitrile and extracted with ethyl acetate. The extracts were evaporated to give the desired compound (25 mg, 31%). LCMS for C24H30N3O3 (M+H)+: m/z=408.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 120 °C
Yield: 44.7 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5 g), 4-nitrothiophenol (4.83 g) and potassium carbonate (7.8 g) in N,N-dimethylformamide (100 ml) was heated at 120° C. for 3 hours with stirring. The reaction mixture was poured into ice-water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of n-hexane and ethyl acetate (3:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(4-nitrophenylthio)thiazole (3.74 g, yield: 50.2%). mp: 250°-255° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[O:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCCCCC>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(C=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
In 4 ml of ethanol was dissolved 440 mg (1.3 mmol)of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 51 mg (1.3 mmol)of sodium borohydride at room temperature. After 10 minutes, the mixture was neutralized by acetic acid and sodium bicarbonate, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was then concentrated under reduced pressure and the residue was recrystallized by isopropyl ether:n-hexane to provide 340 mg (yield 77%)of Compound I-8. mp 157 to 158° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:24]=1)[NH2:23]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([NH:23][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Cc1ccc(Cl)cc1N
Product: Cc1ccc(Cl)cc1Nc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 78.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 5-chloro-2-methylaniline (80 mg, 0.56 mmol) to provide 206 (113 mg, 78% yield) as a white solid. LC-MS (M+H=336, obsd.=336).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:8][C:7](=[O:20])[C:6]([O:21][CH3:22])=[CH:5]2
Reactant: COC(=O)CBr
Reactant: COc1cc2cc(N)c(OCc3ccccc3)cc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-amino-7-benzyloxy-3-methoxychromen-2-one (0.880 g, 2.96 mmol) and K2CO3 (0.820 g, 5.92 mmol) in DMF (50 mL) is added methyl bromoacetate (0.36 mL, 3.85 mmol). The mixture is stirred at 60° C. for 3 h. Additional methyl bromoacetate (0.14 mL) is added, and after 3 h, the mixture is allowed to cool to ambient temperature and poured into water and extracted with EtOAc. The organic layer is washed with water (3×), sat. NaCl, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using hexanes/EtOAc (7:1) to afford (7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-ylamino)-acetic acid methyl ester as a yellow solid: 1H NMR (CDCl3) δ 7.44-7.33 (m, 5H), 6.79 (s, 1H), 6.75 (s, 1H), 6.36 (s, 1H), 5.13 (s, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H); (M+H)+=370.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@H:14]2[CH2:17][CH2:16][O:15]2)(=O)=O)=CC=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CS(C)=O>[N:18]([CH2:12][CH2:13][C@H:14]1[CH2:17][CH2:16][O:15]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H]2CCO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC[C@H]1CCO1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
The mixture of (R)-2-(oxetan-2-yl)ethyl 4-methylbenzenesulfonate (80 mg, 0.31 mmol), NaN3 (30 m2, 0.465 mmol) and KI (5 mg) in DMSO (1 mL) was heated to 55° C. and stirred for 18 h. Then the mixture was cooled to RT, then it was poured into 20 mL of water, then extracted with MTBE (20 mL×3), the organic layers was washed with 1-120 (10 mL), brine (10 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. to give the titled compound which was used to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:22])[NH:15][C:14]([CH2:23][O:24][CH2:25][CH:26]2[CH2:30][O:29]C(C)(C)[O:27]2)=[C:13]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)(=O)C>[OH2:19].[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:22])[NH:15][C:14]([CH2:23][O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])=[C:13]1[C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:22])[NH:15][C:14]([CH2:23][O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])=[C:13]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)C1=C(COCC2COC(C)(C)O2)NC(C)=C(C(=O)OC)C1c1cccc(C(F)(F)F)c1Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(COCC(O)CO)NC(C)=C(C(=O)OC)C1c1cccc(C(F)(F)F)c1Cl
Product: O

Procedure:
1-{[4-(2-Chloro-3-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2,3-dihydroxypropane hemihydrate was prepared by the method described in the previous Example 4-{[4-(2-chloro-3-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxymethyl}-2,2-dimethyl-1,3-dioxolane and 60% aqueous acetic acid. The product was characterised as a hemihydrate, m.p. 114° C.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:18][NH3+:19]>N1C=CC=CC=1>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[N:19][OH:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C1CC(c2ccccc2)c2ccccc21
Yield: 62.7 %

Procedure:
A mixture of 3-phenyl-1-indanone (4.2 g, 20 mmol, J. Chem. Soc. 1949, 2957), hydroxylammonium chloride (2.8 g, 40 mmol) and pyridine (30 ml) was heated at reflux overnight. The reaction mixture was allowed to cool and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with excess 10% citric acid solution. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo to give a solid which was triturated with a mixture of cyclohexane and ethyl acetate. The solid was isolated by filtration and dried in air to give 2.8 g of 3-phenyl-1-indanone oxime as a solid. M.p. 123°-125° C.
Reaction SMILES: I[C:2]1[N:14](S(C2C=CC(C)=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.CO>[CH3:13][N:10]1[C:9]2=[C:4]3[CH:3]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[NH:14][C:5]3=[N:6][CH:7]=[C:8]2[CH:12]=[N:11]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)cn1
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A flask was charged with 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.134 g, 0.296 mmol, Example #41, Step C), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.074 g, 0.36 mmol), (PPh3)4 (0.024 g, 0.021 mmol, Strem) and Na2CO3 (0.079 g, 0.74 mmol) in 1,4-dioxane:water (3:1, 10 mL) The reaction was heated at about 80° C. for about 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a solid that was added to a 5 mL microwave reaction vial. MeOH (3 mL) and aqueous NaOH (5 N, 0.77 ml, 3.8 mmol) were added and the reaction vessel was sealed and heated to about 120° C. in a microwave for about 20 min (250 psi maximum pressure, 2 min ramp time, 300 max watts). The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated, redissolved in MeOH/DCM, and purified by silica gel chromatography (12 g column) eluting with a gradient of 0-5% MeOH in DCM. The product-containing fractions were combined and concentrated to give 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.038 g, 39% over 2 steps): LC/MS (Table 2, Method d) Rt=1.13 min; MS m/z: 253 (M+H)+.
Reaction SMILES: Cl[CH2:2][Si:3]([O:6][CH3:7])([CH3:5])[CH3:4].[O-:8][C:9]#[N:10].[K+].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>CN(C=O)C>[CH3:7][O:6][Si:3]([CH2:2][NH:10][C:9]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[O:8])([CH3:5])[CH3:4]
Reactant: O=C1CCCN1
Reactant: CO[Si](C)(C)CCl
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO[Si](C)(C)CNC(=O)N1CCCC1=O
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of 69.3 g of (chloromethyl)methoxydimethyl-silane, 40.6 g of potassium cyanate and 42.6 g of 2-pyrrolidinone in 150 ml of anhydrous DMF was heated at 130° C. with stirring for 5 h. The solvent was then removed under reduced pressure. This gave N-[(methoxydimethylsilyl)methyl]-2-oxo-1-pyrrolidinecarboxamide in quantitative yield with a purity of >90% (analysis by 1H NMR, see Example 2a).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:42])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([NH:31]C(=O)OC(C)(C)C)=[CH:30][C:24]=4[S:23](=[O:40])(=[O:39])[N:22]=3)[C:11]2=[O:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:43]>O1CCOCC1>[ClH:43].[NH2:31][C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:21]([C:12]3[C:11](=[O:41])[C:10]([CH2:9][CH2:8][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)([CH3:42])[C:19]4[C:14]([C:13]=3[OH:20])=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:22][S:23](=[O:40])(=[O:39])[C:24]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCCC3CCCCC3)C1=O)N2
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 70 %

Procedure:
A solution of Example 38A (0.570 g, 0.960 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.357 g, 70%).
Reaction SMILES: [SH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]([OH:16])(=[O:15])[C:12]#[C:13][CH3:14]>>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([S:1]/[C:13](/[CH3:14])=[CH:12]\[C:11]([OH:16])=[O:15])=[CH:3]1
Reactant: CC#CC(=O)O
Reactant: Sc1c[nH]c2ccccc12
Product: C/C(=C/C(=O)O)Sc1c[nH]c2ccccc12

Procedure:
By the same method as described in Example 1, 0.2 mole each of 3-mercaptoindole and tetrolic acid gives 10.2 g of product after recrystallization from acetonitrile, mp 201°-202° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:29])=[O:28])[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl.[N:45]1(C(N)=N)C=CC=[N:46]1>C(Cl)Cl>[NH2:45][N:46]=[CH:6][N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:28])=[O:29])[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:21]=2)[CH2:12][CH2:13]1
Reactant: N=C(N)n1cccn1
Reactant: COC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
2-Chlorobenzenesulfonic acid 3 -[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]-5-carbomethoxyphenyl ester (0.14 g, 0.26 mmol), as prepared in the preceding step, was treated with 2.5 mL of 25% trifluoroacetic acid in methylene chloride at ambient temperature for 15 min. The solvent was evaporated, the residue was azeotroped with acetonitrile (2 times), and placed under high vacuum. The residue was dissolved in methanol (3 mL) and treated with 1H-pyrazole-1-carboxamidine hydrochloride (0.057 g, 0.39 mmol) and N,N-duisopropylethylamine (0.136 mL, 0.78 mmol). The reaction mixture was stirred at ambient temperature overnight. An additional portion of 1H-pyrazole-1-carboxamidine hydrochloride (10 mg) was added to the reaction mixture and then was stirred for 6 h. The solvent was evaporated to dryness. The residue was triturated with hexane and ether. The residue was dissolved in acetonitrile and diluted with diethylether to produce a crystalline crop, which was collected by filtration to give 25.3 mg of solid. 1H-NMR (CDCl3 ; 300 MHz): δ 1.44-1.55 (m, 2H), 1.95-2.1 (m, 3H ), 3.11 (t, 2H ), 3.81 (d, 2H), 3.87 (s, 3H), 4.07 (d, 2H), 6.90 (t, 1H), 7.38 (m, 5H), 7.64 (m, 2H), 7.96 (m, 1H). Mass spectrum MADLDI-TOF) calcd. for C21H24N3O6SCl: 482.1 (M+H). Found 483.5.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1>>[ClH:1].[CH:13]1([NH:21][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:24]3[C:23]([CH3:22])=[CH:27][C:26]([CH3:28])=[N:25]3)[N:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: NC1CCCCCCC1
Product: Cc1cc(C)n(-c2nc(NC3CCCCCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclooctylamine and 3,5-dimethylpyrazole. Mp. 211° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCCCCCCCCCCCCCC.[Mg].II.[CH3:43][Si:44]([CH3:53])([CH3:52])[C:45]1[O:49][CH:48]=[C:47]([CH:50]=[O:51])[CH:46]=1>C(OCC)C.O1CCCC1>[OH:51][CH:50]([C:47]1[CH:46]=[C:45]([Si:44]([CH3:53])([CH3:52])[CH3:43])[O:49][CH:48]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Br
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: CCCCCCCCCCCCCCCCCCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of octadecylmagnesium bromide (10.2 ml of a 0.34M solution in ethyl ether, 3.46 mmol, generated from 1-bromooctadecane and magnesium using iodine as an initiator) at 0° under argon, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.265 g., 1.57 mmol) in 2 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and quenched with a 5% ammonium chloride solution. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with 10% sodium bisulfite, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a residue. This was taken up in ethyl ether and filtered. The ether portion was concentrated to give a waxy residue which was purified by flash chromatography (silica, 10% ethyl ether/petroleum ether) to give the desired alcohol.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[N:4]=1)=[CH2:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:1][C:3]2[O:7][N:6]=[C:5]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[N:4]=2)[CH2:21][CH2:20]1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Reactant: CC1CCNCC1
Solvent: CO
Product: CC1CCN(CCc2nc(-c3cn(C)c4ccccc34)no2)CC1
Reaction time: 16 h

Procedure:
5-Ethenyl-3-(1-methyl-1-H-indol-3-yl)-1,2,4-oxadiazole (D2)(0.0254 g, 1.13 mmol) was dissolved in methanol (5 ml) and 4-methyl piperidine (0.167 ml, 1.69 mmol) was added. The mixture was left standing at room temperature for 16 hours, before being evaporated under reduced pressure to give a colourless oil, which was purified by silica-gel chromatography, eluting with ethyl acetate to afford the title compound as a colourless oil that crystallised on standing. The material was then converted to its hydrochloride salt, mp 192°-192° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH:14](=O)[CH2:15][CH3:16]>ClCCl>[CH2:15]([CH:16]1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:14]
Reactant: OCCNCCO
Reactant: CCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC1OCCN1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a 250 mL flask containing diethanolamine (2,9 mL, 30 mmol d=1,0955) in dichloromethane (60 mL) under nitrogen atmosphere, was added potassium carbonate (8,3 g, 60 mmol, 2 eq.) before adding at 0° C. dropwise propionaldehyde (2,73 mL, 37,5 mmol, 1,25 eq.). The reaction was warmed to room temperature and stirred for 3 h. The potassium carbonate was filtered with a sinter funnel and washed several times with dichloromethane. After evaporation of the combined organic phases, 4,994 g of crude product was obtained. The product was purified by distillation under vacuum to give the title compound (3,87 g, 87% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,93 (dd, J=4,3 Hz, J=6,4 Hz, H); 3,92-3,82 (m, 2H); 3,71-3,58 (m, 2H); 3,26 (ddd, J=5,5 Hz, J=6,5 Hz, J=12,2 Hz, H); 2,83 (ddd, J=4,9 Hz, J=8,2 Hz, J=12,7 Hz, H); 2,66 (dt, J=7,0 Hz, J=10,0 Hz, H); 2,55 (dt, J=3,9 Hz, J=12,2 Hz, H); 1,60 (ddq, J=4,3 Hz, J=7,4 Hz, J=14,1 Hz); 1,51 (ddq, J=6,4 Hz, J=7,4 Hz, J=14,1 Hz); 0,95 (t, J=7,4 Hz, 3H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 97,5; 64,1; 60,0; 55,1; 51,7; 26,8; 8,9.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][NH:22][CH2:23][CH2:24][NH2:25]>C(O)CCC.O>[CH3:21][N:22]1[C:5]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:14])[NH:25][CH2:24][CH2:23]1
Reactant: CNCCN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 80 °C
Yield: 22.2 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (500 mg, 2.32 mmol) was dissolved in n-butanol (2.5 ml). Na2CO3 (246 mg, 2.32 mmol) was added followed by N, methylethylenediamine (204 μL, 2.32 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, and concentrated. Silica gel chromatography (0-100% EtOAc in hexanes) afforded 1-Methyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a bright orange solid (114 mg, 24%). Cmp 183-184° C.; LCMS: m/z=222.25 (M+H+) 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 1H), 8.32 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.15 (dd, J=7.8 Hz, 1.5 Hz, 1H), 6.78 (t, J=8.3 Hz, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.20 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([O-])[CH:4]=[C:3]([CH2:8][C:9]#[N:10])[CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:3]([CH2:8][C:9]#[N:10])=[CH:2][CH:1]=[CH:6][N:5]=1
Reactant: N#CCc1ccc[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: N#CCc1cccnc1Cl
Temperature: 5 °C
Yield: 42.9 %

Procedure:
(1-oxypyridin-3-yl)acetonitrile (7.5 g, 35.9 mmol) is carefully added to vigorously stirred phosphorous oxychloride (100 mL). The mixture is slowly heated to 80° C. (in 5° C. increments) over 1.5 hr. (CAUTION. If heating is too quick, violent decomposition occurs at ca 70° C.) All the solids dissolved. The reaction is heated at reflux for 3 hr. The excess phosphorous oxychloride is removed and the residue is cautiously treated with cold water. Saturated sodium bicarbonate is added to make the mixture basic, then it is extracted with ethyl acetate (3×). The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10 to 100% ether. The second compound off the column is the desired (2-chloropyridin-3-yl)acetonitrile (2.35 g, 42.9% yield) a light brown solid.