Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7](SC)=[N:8][CH3:9].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)[CH2:19][CH2:18]1>CC(O)C>[IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)[CH2:19][CH2:18]1)=[N:8][CH3:9]
Reactant: CN=C(NCC(OC)OC)SC
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: I
Solvent: CC(C)O
Product: CN=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)NCC(OC)OC
Yield: 99 %

Procedure:
A mixture of 12.8 parts of methyl N-(2,2-dimethoxyethyl)-N'-methylcarbamimidothioate monohydroiodide, 13.2 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and 160 parts of 2-propanol was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 23 parts (99%) of N-(2,2-dimethoxyethyl)-N'-[2-[4[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N"-methylguanidine monohydroiodide (195).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:8]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:10][CH2:11][CH:12]=[CH2:13])=[N:4][CH:5]=[CH:6][N:7]=1.[C:30]([O:34][CH3:35])(=[O:33])C=C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C@@H:8]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:30]([O:34][CH3:35])=[O:33])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=CC(=O)OC
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Solvent: ClCCl
Product: COC(=O)/C=C/CC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Yield: 84.1 %

Procedure:
In a 250 mL round-bottomed flask was dissolved tert-butyl (1S,2S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-enylcarbamate (354.6 mg, 0.757 mmol) in methylene chloride (16 mL) to give a colorless solution. Methyl acrylate (0.21 mL, 2.3 mmol) and Grubbs-If catalyst (32.1 mg, 0.038 mmol) were added, and the mixture was stirred under reflux for 3 h under nitrogen. TLC showed complete conversion. Volatile components were removed in vacuo and the residue was purified by flash column chromatography upto 50% ethyl acetate/hexane to afford the desired product (335 mg, 84%) as a colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (s, 1H) 8.28 (s, 1H) 6.98-7.14 (m, 3H) 6.80-6.94 (m, 1H) 5.76 (d, J=16.56 Hz, 1H) 5.59-5.71 (m, 1H) 5.42 (d, 0.1-9.54 Hz, 1H) 3.71 (s, 3H) 3.59-3.69 (m, 1H) 2.09-2.29 (m, 2H) 1.96-2.04 (m, 1H) 1.83-1.95 (m, 1H) 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(trifluoromethyl)aniline (0.772 mL, 6.21 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.47 g, 12.4 mmol) in acetic acid (30 mL) was treated with anhydrous Na2SO4 powder (8.82 g, 62.1 mmol). The mixture was stirred at ambient temperature for 20 minutes, and then sodium triacetoxyborohydride (3.95 g, 18.6 mmol) was added in approximately 5 equal portions over 2 minutes. The reaction was allowed to proceed at ambient temperature for 3 hours. The reaction mixture was carefully poured into a well-stirred mixture of 1:1 ethyl acetate/hexanes (100 mL) and saturated NaHCO3 solution (150 mL), and then basified with excess 2 N aqueous NaOH solution. The phases were separated, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with hexanes and the solid was collected by vacuum filtration and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.35 (d, J=8.6, 2H), 6.69 (d, J=8.6, 2H), 6.25 (d, J=8.0, 1H), 3.95-3.80 (m, 2H), 3.56-3.40 (m, 1H), 3.02-2.81 (m, 2H), 1.94-1.80 (m, 2H), 1.40 (s, 9H), 1.33-1.18 (m, 2H); MS (DCI+) m/z 345 (M+H)+.
Reaction SMILES: [Li].[H-].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].Cl>C(OCC)C.O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[CH2:16][OH:17]
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1Cc1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc(COc2ccccc2)cc1Cc1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To the suspension of zinc (710 mg) in tetrahydrofuran (2 ml) was added dibromoethane (1 drop) under an atmosphere of argon. The mixture was heated and then added trimethylsilyl chloride (1 drop). The reaction mixture was cooled to 0° C. and added dropwise a solution of 2-bromomethylnaphthalene (1.20 g) in tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 1.5 hour to give the zinc reagent. To a solution of [bis(benzylidene)acetone]palladium (156 mg) and diphenylphosphinoferrocene (151 mg) in tetrahydrofuran (2 ml) was added the compound prepared in Reference Example 17 (1.00 g) in tetrahydrofuran (3 ml) under an atmosphere of argon. To the mixture was added the above-mentioned zinc reagent. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give methyl 2-(2-naphthylmethyl)-4-phenoxymethylbenzoate. To a suspension of lithium alminium hydride (206 mg) in (2 ml) was added dropwise a solution of the above-mentioned methyl 2-(2-naphthylmethyl)-4-phenoxymethylbenzoate in diethyl ether (3 ml)-tetrahydrofuran (3 ml) under an atmosphere of argon. The mixture was stirred for 30 minutes. To the mixture was added 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (974 mg) having the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[C:23]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:43][CH2:42]2)=[CH:24][C:25]([Cl:40])=[C:26]([CH:39]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38])=[O:28].[Cl-].[Li+]>CN(C=O)C>[Cl:40][C:25]1[C:26]([C:27](=[O:28])[NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:39][C:22]([NH:21][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:23]([N:41]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:45][CH2:46]2)[CH:24]=1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid 1h (122.2 mg, 0.79 mmol) in DMF (5.0 mL) HATU (404.4 mg, 1.06 mmol) was added and stirred for 3 min. N,N-diisopropylethylamine (0.46 mL, 2.66 mmol) was added to this followed by 5-amino-2-chloro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 1g (250.0 mg, 0.53 mmol) in DMF (5.0 mL) and the reaction was stirred at 25° C. for 16 h. LCMS indicated the completion of reaction. Saturated solution of lithium chloride was added to this and the contents were extracted with ethyl acetate, organic layer was dried on anhydrous sodium sulfate, concentrated and the crude ii was purified on preparative HPLC using water/methanol (0.1% TFA) (42.0 mg, 13%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:18][C:19]1[C:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:23]([CH3:33])[N:22]=[C:21]([O:34][CH2:35][C:36]([N:38]([CH3:45])[CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:37])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:3]1([CH2:2][N:42]2[CH2:41][CH2:40][CH:39]([N:38]([CH3:45])[C:36](=[O:37])[CH2:35][O:34][C:21]3[N:20]=[C:19]([CH3:18])[C:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[C:23]([CH3:33])[N:22]=3)[CH2:44][CH2:43]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCCCC1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Bromomethyl cyclohexane (25 μL) and diisopropylethylamine (63 μL) were added to a solution of Compound 31 (71 mg) in dimethylformamide (1 mL) and the mixture was stirred at 120° C. for 8 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (hexane: ethyl acetate=1:1) to give 40 mg (46% yield) of the desired product.
Reaction SMILES: [C:1](=[O:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3]Cl.[I-:13].[Na+]>CC(C)=O>[C:1](=[O:12])([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3][I:13]
Reactant: O=C(OCCl)OC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCI)OC1CCCCC1

Procedure:
A solution of 0.78 g of chloromethyl cyclohexyl carbonate and 1.0 g of sodium iodide in 15 ml of acetone is stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is extracted with ether and the solvent is distilled off under reduced pressure to give the title compound as pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].[BH4-].[Na+]>C(O)C>[OH:11][CH:10]1[CH2:9][CH2:8][C@H:7]([CH2:12][C:13]([OH:15])=[O:14])[C@H:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC1C(=O)CCC1CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC[C@H]1C(O)CC[C@@H]1CC(=O)O

Procedure:
This compound was prepared in a way similar to that described in operation 2 of Example 1, by reacting dihydrojasmonic acid with sodium borohydride, NaBH4, in ethanol at 50° C. for 4 hours.
Reaction SMILES: [Li:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1>[Li:1].[C-:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: [c-]1cccc2ccccc12
Reaction time: 0.08 h
Yield: 34 %

Procedure:
A mixture of lithium (12 mg, 1.73 mmol) and naphthalene (222 mg, 1.73 mmol) was stirred in THF (2.5 mL) at room temperature for 4 hours. As a result, a lithium-naphthalenide solution was prepared. To the solution, a solution in which Intermediate (VI) (130 mg, 0.41 mmol) was mixed with THF (1 mL) was added at room temperature. Immediately after the reaction mixture had been stirred for 5 minutes, the reaction mixture was mixed with a saturated ammonium chloride solution.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H)
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:21]#[N:22])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[CH:10][CH:11]=1.O.O.Cl[Sn]Cl>O.Cl>[F:19][C:17]1[CH:18]=[C:13]([NH:12][C:9]2[N:8]=[C:7]3[C:21]([NH2:1])=[N:22][NH:5][C:6]3=[CH:11][CH:10]=2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: O=N[O-]
Reactant: N#Cc1nc(Nc2cc(F)cc(F)c2)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(Nc3cc(F)cc(F)c3)nc12
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
A solution of 713 mg of NaNO2 (10.3 mmol) in water (5 ml) is added, drop by drop, to a stirring solution of 2.3 g of 3-amino-6-(3,5-difluorophenylamino)picolinonitrile (9.4 mmol) in 100 ml of 6 N hydrochloric acid at 0° C. The mixture is stirred for 20 minutes at 0-5° C. A solution of 5.3 g of SnCl2.2H2O (23.5 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 30 ml) is then added drop by drop and the solution is stirred for 1 hour at room temperature. The reaction medium is then cooled at 0° C. and basified to pH 8 using 30% soda solution. The mixture is extracted with ethyl acetate and washed using saturated NaCl solution and the organic phase is dried on anhydrous sodium sulfate before being concentrated under vacuum. The residue is purified by silica column chromatography (AcOEt). A light yellow solid is obtained (530 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][CH2:3][CH:23]([C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(C)=O
Reactant: CCCSc1ncc(CCCl)n1Cc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCCSc1ncc(CCC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 71 %

Procedure:
The procedure of Example 3(iv) was followed using 5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazole hydrochloride in place of 5-chloromethyl-1-[(2-chlorophenyl)methyl]2-propylthio-1H-imidazole hydrochloride. The title compound was obtained in 71% yield after chromatography over silica gel with a gradient of ethyl acetate in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[Li+].[BH4-]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(N)ncn1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Nc1cc(CO)ncn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a stirred solution of methyl 6-aminopyrimidine-4-carboxylate (2.0 g, 13 mmol) in MeOH (20 mL) at 25° C., was added LiBH4 (0.85 g, 39 mmol). After addition, the resulting mixture was allowed to stir at 70° C. for 16 hours. TLC indicated the starting material was consumed completely at this point. Solvents were removed under reduced pressure and the residue was purified via chromatography column on silica gel eluting with a 5% gradient of methanol in dichloromethane to give the desired alcohol as pale yellow oil (1.0 g, 61% yield). LCMS (ESI) m/z: 126.1 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[CH2:17]([N:21]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:22]([C:24]1[CH:46]=[CH:45][C:27]2[N:28]([CH2:32][CH2:33][CH2:34][N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:29](=[S:31])[NH:30][C:26]=2[CH:25]=1)=[O:23])[CH:18]([CH3:20])[CH3:19]>O1CCCC1>[CH2:47]([N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:22]([C:24]1[CH:46]=[CH:45][C:27]2[N:28]([CH2:32][CH2:33][CH2:34][N:35]([CH3:44])[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:29]([S:31][CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=3)=[N:30][C:26]=2[CH:25]=1)=[O:23])[CH:48]([CH3:49])[CH3:50]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CSc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Morpholinomethylpolystyrene resin (acquired from Novabiochem, 2 eq) and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone are added successively to a solution of N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamide in tetrahydrofuran. The mixture is stirred for 15 hours at approximately 20° C. then tetrahydrofuran, aminomethylpoystyrene resin (2 eq, acquired from Novabiochem) and 4-bromomethylphenoxymethyl-polystyrene resin (3 eq, acquired from Novabiochem) are added. After stirring for 6 hours, the mixture is filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. in order to produce the expected compound.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH2:10][CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CN(C=O)C>[Cl:19][C:18]1[C:13]([CH:5]([C:4](=[O:3])[CH2:10][CH3:11])[C:6]([O:8][CH3:9])=[O:7])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
4.45 g of potassium hydroxide 85% are suspended in 40 mL of DMF, 4.37 g of methyl 3-oxopentanoate (0.036 mol) are subsequently added. The reaction mixture is warmed to 50° C. and 6 mL of 2,3-dichloro-5-(trifluoromethyl)pyridine are introduced. The reaction mixture is stirred at 50° C. for 4 hours, quenched with 150 mL of an aqueous solution of NaH2PO4 (1M), extracted thrice with 150 mL of ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=3)[CH:20]=[CH:19][C:18]=2[F:33])[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.CO[CH:38](OC)[N:39]([CH3:41])[CH3:40]>CN(C)C=O>[CH3:38][N:39]([CH3:41])/[CH:40]=[CH:29]/[C:27]1[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([F:33])=[C:17]([CH:22]=2)[CH2:16][N:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6](=[O:7])[C:5]2[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=2)[CH:28]=1
Reactant: Cc1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2ccc(F)c(CN(CCN3CCCC3)C(=O)c3ccc(F)cc3)c2)ncc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 72.4 %

Procedure:
4-Fluoro-N-[2-fluoro-5-(4-methyl-5-nitro-pyridin-2-yl)-benzyl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide (prepared according to example 20, 600 mg, 1.25 mmol) in 15 mL of dimethylformamide was treated with dimethylformamide dimethyl acetal (0.23 mL, 1.68 mmol), and the resulting mixture was heated at 80° C. for 5 h. The mixture was allowed to cool and the volatiles were removed. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to give an oil. The above process was repeated to give 485 mg of product.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O-]CC.[Na+].[Br:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1.O>C(O)C>[Br:38][C:39]1[CH:46]=[CH:45][C:42](/[CH:43]=[CH:14]/[C:4]2[N:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:7][C:3]=2[CH3:2])=[CH:41][CH:40]=1
Reactant: Cc1oc(-c2ccccc2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
(5-Methyl-2-phenyl-4-oxazolylmethyl)triphenyl-phosphonium chloride (25.4 g) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (1.4 g) and ethanol (300 ml)] under cooling. The mixture was stirred at room temperature for 5 minutes, and then 4-bromobenzaldehyde (10.0 g) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ether-hexane (1:20, v/v) gave (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.1 g, 71%). This product was recrystallized from ethyl acetate-hexane. Colorless prisms, mp: 138-139° C.