Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]([CH2:22][NH2:23])[CH2:10]1.[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([Cl:35])=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]([CH2:22][NH:23][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=2)[CH2:10]1
Reactant: COc1ccccc1N1CCN(Cc2ccccc2)C(CN)C1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2)C(CNC(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Product: Cl

Procedure:
In a manner similar to Preparation 3, react 4-(2-methoxyphenyl)-1-(phenylmethyl)-2-piperazinemethanamine (3.8 g, 12 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (3.2 g, 14 mmol) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)=O.C(O)(=O)C>O>[C:11]([C:7]1[CH:8]=[C:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: COc1ccc(CO)cc1
Solvent: O
Solvent: O=CO
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
2,6-Di-t-butyl-4-(4-methoxybenzyl) phenol was prepared as described for A above. A mixture of 2,6-di-t-butylphenol (51.5 g), 4-methoxybenzyl alcohol (34.5 g), formic acid (100 ml) and acetic acid (100 ml) was refluxed for 5 hours, diluted with water, and extracted with chloroform. Evaporation of the chloroform gave an oil which crystallized. Recrystallization from methanol gave colorless needles, mp. 139° (58 g); (Found: C, 80.7; H, 9.30. Calc. for C22H30O2 : C, 80.9; H, 9.26%); pmr spectrum: δ1.42, 18H, S; δ3.79, 3H, S; δ3.86, 2H, S; δ5.04, 1H, S; δ6.83, 2H, D (J=8 Hz), δ6.98, 2H, S; δ7.12, 2H, D (J=8 Hz).
Reaction SMILES: [I-].C[CH:3]=[N+:4]=[CH:5]C.[CH3:7][C:8]1[N:9]=[C:10]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]2[C:22]=1[CH3:23].[C:24](=O)([O-])O.[Na+]>ClCCl>[CH3:7][C:8]1[N:9]=[C:10]2[C:15]([OH:16])=[C:14]([CH2:3][N:4]([CH3:5])[CH3:24])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]2[C:22]=1[CH3:23]
Reactant: CC=[N+]=CC
Reactant: CCOC(=O)c1cc(O)c2nc(C)c(C)n2c1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(C)c(C)nc2c(O)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Over a period of 30 minutes, N,N-dimethylmethyleneammonium iodide (Eschenmoser's salt, 435 mg, 2.35 mmol) is added to a solution of ethyl 2,3-dimethyl-8-hydroxy-imidazo[1,2-a]pyridine-6-carboxylate (500 mg, 2.14 mmol) in 15 ml of dichloromethane. The reaction mixture is stirred for 2.5 hours at ambient temperature and the formation of a colourless precipitate is observed. 20 ml portions of saturated sodium hydrogencarbonate solution and dichloromethane are added to the reaction mixture. The aqueous phase is extracted with dichloromethane (3×20 ml). The combined organic phases are washed with water (20 ml), dried over sodium sulfate, and evaporated to dryness. The title compound (578 mg, 93%) is isolated as a greenish foam containing traces of impurities.—1H NMR (CDCl3, 200 MHz): □=1.41 (t, 3 H), 2.40 (s, 12 H), 4.19 (s, 2 H), 4.37 (q, 2 H), 8.04 (s, 1 H).
Reaction SMILES: I.[C:2]1([NH:8][C:9](=[NH:12])[NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:35])[CH2:21][CH2:22][C@@H:23]2[CH:33]=O)[CH2:15]1>O.O1CCOCC1>[C:2]1([NH:8][C:9](=[NH:12])[NH:10]/[N:11]=[CH:33]/[C@H:23]2[CH2:22][CH2:21][C@:20]3([OH:35])[C@H:19]4[C@H:28]([CH2:27][CH2:26][C@:24]23[CH3:25])[C@:29]2([CH3:32])[C@@H:16]([CH2:15][C@@H:14]([OH:13])[CH2:31][CH2:30]2)[CH2:17][CH2:18]4)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NN)Nc1ccccc1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/NC(=N)Nc3ccccc3)CC[C@]12O
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To a solution of 0.83 g of 3-phenyl-1-aminoguanidine hydroiodide (prepared following the procedure described in Houben-Weil, Metoden der Organischen Chemie, Band VIII, page 183) in 10 ml of water and 5 ml of dioxane a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 5 ml of dioxane was added dropwise at room temperature. After 2 hrs, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 89/10/1 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethanol to give 0.20 g of the title compound (I-ah) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:25])=[O:24])(=[O:16])=[O:15]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methylsulfonylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.4 mg) with purity >90%. MS (pos) m/z 405.4.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(CO)NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc(C(N)=O)cn1)NCc1ccccc1

Procedure:
Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1 a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([CH3:14])C(O)=O)[CH:5]=[CH:6][C:7]=1Cl.BrC1C=CC([C:22]([F:25])([F:24])[F:23])=C(Cl)C=1.BrCC[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:33]([O:32][C:30](=[O:31])[CH2:14][CH2:10][NH:9][C:4]1[CH:5]=[CH:6][C:7]([C:22]([F:23])([F:24])[F:25])=[C:2]([Cl:1])[CH:3]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Reactant: C[C@@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CC(C)(C)OC(=O)CCNc1ccc(C(F)(F)F)c(Cl)c1
Yield: 53 %

Procedure:
In analogy to the procedure described for intermediate 31, 4-bromo-2-chloro-1-trifluoromethyl-benzene and tert-butyl 3-bromopropionate gave the title compound in 53% yield as yellow oil. MS: 323 (M+, Cl).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[N:15]([CH:17]([CH3:18])[CH3:19])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(Cc1ccccc1)C2
Yield: 27.7 %

Procedure:
The title compound (72 mg) was prepared according to Example 287 using 300 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 146 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C22H24FN3, 349.20. found, m/z 350.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.57 (m, 2H), 7.55-7.53 (m, 3H), 7.43-7.40 (m, 2H), 7.32-7.27 (m, 2H), 4.59-4.34 (m, 5H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.90-2.85 (m, 2H), 1.43-1.36 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Li+].Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[CH:16]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:15]3[CH:16]=[C:17]([O:23][CH3:24])[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chlorooxindole (0.94 g, 5.34 mmol) (Cresent Chem.) in N,N-dimethylformamide (20 mL) at room temperature was added lithium hydride (86 mg, 10.7 mmol) (Aldrich). The mixture was stirred at room temperature for 10 minutes, then 6-chloro-2,4-dimethoxy-pyrimidine (0.93 g, 5.34 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The mixture was cooled to room temperature. Water (100 mL) was added, and mixture was extracted with ethyl acetate (2×100 mL). The organic layers were separated, combined, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate) to give rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.23 g, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: Brc1nccs1
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1Oc1nccs1
Temperature: 150 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of 4-bromo-2-ethyl-phenol (1.00 g, 4.97 mmol) in DMF (40 mL) was added 2-bromothiazole (0.341 mL, 3.82 mmol) and finely crushed K2CO3 (3.17 g, 22.9 mmol). The mixture was stirred at 150° C. for 15 hours, at which time the hot solution was filtered through filter paper. The filtrate was diluted with CH2Cl2 and H2O and then brought to pH 6.0 with 6.0N HCl. The aqueous layer was extracted with CH2Cl2 and the organic layer was washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated to yield a yellow oil (1.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.5 Hz, 2H), 6.79 (d, J=3.8 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.19 (d, J=3.8 Hz, 1H), 7.35 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16](C(O)=O)[CH3:17].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:16]([CH3:17])[NH:15][CH:26]2[C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CC(N)C(=O)O
Reactant: O=Cc1ccc(Br)cc1
Product: CC1NC(c2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C12

Procedure:
(3aRS,4SR,6RS,6aSR)-2-Benzyl-4-(4-bromo-phenyl)-6-methyl-tetrahydro -pyrrolo[3,4-c]pyrrole-1,3-dione was prepared from N-benzylmaleimide, D,L-alanine and 4-bromobenzaldehyde in an analogous manner to Example 2.a). 47% were isolated as colourless crystals. M.p.: 170°-172° C. FAB-MS: 799 ([2M+3H]+, 10); 552 (3); (399 ([M+H]+, 100); 238 (9); 211 (29); 91 (61).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([NH2:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18]>CN(C=O)C>[NH2:8][C:5]1[N:6]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:7]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1n[nH]c(N)n1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(N)n(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Methylsulfanyl-2H-[1,2,4]triazol-3-ylamine (0.216 g, 1.7 mmol) was taken in dry DMF (15 ml) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded crude product that was purified by column chromatography (CHCl3/MeOH): 1H NMR (300 MHz, DMSO-d6): δ 7.24 (d, 2H), 6.98 (d, 2H), 6.24 (s, 2H), 4.84 (s, 2H), 3.57 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [Na].[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16](O)=O)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.Br[C:20](C)(C=C)[C:21]([O-])=O.ClCCl.[C:30]([O:33][CH2:34]C)(=[O:32])C>>[CH3:20][C:21]1[C:16]([C:30]([O:33][CH3:34])=[O:32])=[C:11]2[N:10]([C:2]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: CCOC(C)=O
Reactant: O=C(O)C1CCCCN1C(=O)c1cccnc1
Reactant: C=CC(C)(Br)C(=O)[O-]
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccnc2)n2c1CCCC2

Procedure:
Methyl 2-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate is prepared as in Example 1, from 2.56 g of the sodium salt of N-nicotinoylpiperidine-2-carboxylic acid and 7.16 g of 2-bromo-2-methylbutenoate. 1.2 g of methyl 2-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate are thus obtained in the form of an orange oil (Rf=0.25; thin layer chromatography on silica gel; eluent: 8/2 dichloromethane/ethyl acetate).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[OH2:8]>C(O)C>[CH2:3]([OH:5])[C@H:2]([C@H:3]([C@@H:2]([C@@H:2]([CH2:3][OH:5])[OH:8])[OH:8])[OH:5])[OH:8]
Reactant: O
Reactant: O=C(O)C(F)(F)F
Solvent: CCO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In a second step the treatment of 0.5 g (0.4 mmol) of the intermediate product 40 dissolved in 4 ml of ethyl alcohol by a trifluoroacetic acid-water mixture (5/1 v/v) yields 0.32 g (70%) of 3,4-di-O-|3'-(F-octyl)-propanoyl|-D-mannitol, 41.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:26]([NH2:27])=[N:25][NH:24][C:21]2=[N:22][CH:23]=1>CN1C(=O)CCC1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]([NH:27][C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([F:17])[CH:19]=3)[NH:24][N:25]=2)[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=1
Reactant: Nc1n[nH]c2ncc(F)cc12
Reactant: Cc1nc(-c2ccccc2Cl)nc(Cl)c1C
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2ccccc2Cl)nc(Nc2n[nH]c3ncc(F)cc23)c1C
Temperature: 135 °C

Procedure:
A mixture of 4-chloro-2-(2-chlorophenyl)-5,6-dimethylpyrimidine (31.14 g, 123 mmol) and 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (19.65 g, 129 mmol) in NMP (200 mL) was heated at 135° C. for 3 h 30 min. Then the mixture was concentrated in vacuo to around 100 mL. Then added sat aq. NaHCO3, water and EtOAc but a precipitate appeared in the organic layer. Filtered off this whole mixture and washed the residue with sat aq. NaHCO3, water and EtOAc and ether. Boiling ethanol was added to the residue with stirring and the pure target compound was filtered. The liquors were concentrated and this trituration procedure repeated 4 times to give the target (25 g, 55%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:23]([CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(O)=O.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[NH:30]1[CH:31]=[CH:32][N:33]=[C:29]1[CH2:28][C:23]1[C:22]([O:21][CH2:20][C:19]2[CH:34]=[CH:35][C:16]([C:11](=[O:12])[NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:17][CH:18]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
Phenyl sulphonyl isocyanate (1.2 g) was added to a suspension of 3-(4-carboxybenzyloxy) 2-(1-imidazolylmethyl)pyridine (1.0 g) in dry tetrahydrofuran (40 ml) containing triethylamine (0.33 g). The mixture was stirred at room temperature for 8 hours and allowed to stand at room temperature for a further 36 hours. The solvents were evaporated under vacuum and aqueous 5% sodium bicarbonate solution (100 ml) added to the residue. The mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts dried, filtered and evaporated to yield an oil which solidified on trituration with diethyl ether. Recrystallization from aqueous methanol gave 2-(1-imidazolylmethyl)-3-[4-(N-phenylsulphonylcarbamoyl)benzyloxy]pyridine (0.38 g), m.p. above 250° C. Found: C, 61.47; H, 4.40; N, 12.63. C23H20N4O4S requires: C, 61.59; H, 4.50; N, 12.49%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[C:34]([CH3:33])[N:35]=[CH:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)cn1
Yield: 32.1 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylimidazole (0.48 g), and dimethylformamide (25 ml), the title compound (0.38 g) was obtained as an amorphous solid, MS, m/z: 403.3 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1)=[O:13]>C(#N)C>[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][CH2:2][CH2:3][S:4][C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: BrCCSc1cccs1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](NCCSc2cccs2)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (275 mg, 1.21 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21 mmol, 1.0 eq) in acetonitrile (6 mL). After 15 hours stirring at 100° C., the reaction mixture is evaporated to afford trans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexanecarboxylic acid methyl ester as an off-white oil (261 mg, 68% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2csc(N)n2)cc1

Procedure:
Prepared by 2 hours' hydrogenation of 2-amino-4-(4-nitro-phenyl)-thiazole (melting point: 287-291° C.; prepared from ω-bromo-4-nitro-acetophenone and thiourea) in DMF on palladium/charcoal (10%) at 20° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[O:3].BrC1C=CC(C(O)=[O:20])=CC=1.C(#N)C=C.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([OH:20])=[O:3]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C=CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CC=Cc1ccc(C(=O)O)cc1
Yield: 35 %

Procedure:
The 4-chloroformylcinnamonitrile can be prepared as follows: 10.05 g (50 mmols) of 4-bromobenzoic acid, 3.31 g (62.5 mmols) of acrylonitrile, 12.6 g (125 mmols) of triethylamine, 0.112 g (0.5 mmol) of palladium acetate, 0.608 g (2 mmols) of tri-o-tolylphosphine and 20 ml of toluene are boiled under reflux for 6 hours. The reaction mixture is extracted by shaking with 100 ml of 2N hydrochloric acid and the crude product is filtered off and recrystallised from methanol. 3 g (35% of theory) of 4-carboxycinnamonitrile are obtained in the form of pale yellow crystals; melting point 281° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[CH2:12]([N:30]=[C:31]=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:12]([NH:30][C:31]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:31]([NH:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:32])=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)NCCCCCCCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with octadecyl isocyanate gave 3,4-bis [[(octadecylamino)carbonyl]oxy]nitrobenzene (mp 117°-121°). The structure was confirmed by the nmr spectrum.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](I)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3].[F:13][C:14]1[C:15]([C:29]2[S:33][C:32]3[C:34](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:36]=[CH:37][C:31]=3[CH:30]=2)=[N:16][C:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:18][CH:19]=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.Cl[Pd]Cl>[N:1]([CH2:4][C:5]1[C:6]([C:34]2[C:32]3[S:33][C:29]([C:15]4[C:14]([F:13])=[CH:19][N:18]=[C:17]([NH:20][CH2:21][CH2:22][N:23]5[CH2:27][CH2:26][NH:25][C:24]5=[O:28])[N:16]=4)=[CH:30][C:31]=3[CH:37]=[CH:36][CH:35]=2)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1cnc(F)cc1I
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 85 °C
Yield: 98.5 %

Procedure:
Combine 5-azidomethyl-2-fluoro-4-iodo-pyridine (70 mg, 0.25 mmol) and 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (100 mg, 0.21 mmol) bis(diphenylphosphino)ferrocene)dichloro palladium (8.5 mg, 0.01 mmol) and NaHCO3 (35 mg, 0.41 mmol) in DMSO (87 mL) and water (3 mL). Purge the mixture through nitrogen for 5 min twice. Heat the mixture at 85° C. for 1 hour in an oil bath. Cool to room temperature. Dilute the reaction mixture with chloroform/isopropyl alcohol 93/1), and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over sodium sulfate. After filtration, remove the organic solvent to give a crude mixture. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the title compound (105 mg, 100%). MS (ES) m/z 508 [M+1]+.