Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1>O1CCOCC1.CO>[N:19]1([C:3](=[O:2])[CH2:4][O:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(COC1CCNCC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 N HCl solution in dioxane (6 mL) was added to a solution of tert-butyl 4-(2-oxo-2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (111) (7.5 g, 22.98 mmol) in MeOH (20 mL) and the reaction mixture was stirred at room temperature for 6 hours. Removal of solvent afforded 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone as its hydrochloride salt (2.300 g, 44.2%). This salt was then dissolved in methanol (50 ml) and MP-carbonate (14.88 g, 33.61 mmol) was added. The resulting mixture was filtered and the solvent removed to give the desired compound (2.300 g, 44.2%), which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=[O:4].CN([CH:11]=[N:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[CH:11]([NH:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1)=[O:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nsc(N=CN(C)C)n3)[C@H]2SC1
Reactant: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nsc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (16.0 ml) was added to a solution of benzhydryl 7-[2-[5-{N-(N,N-dimethylaminomethylene)amino}-1,2,4-thiadiazol-3-yl]-2-tertbutoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.0 g) in methylene chloride (8.0 ml) and anisole (4.0 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to diisopropyl ether (200 ml), and the precipitated substance was collected by filtration and then added to a mixture of water and ethyl acetate, followed by adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was saturated with sodium chloride and adjusted to pH 2.5 with 10% hydrochloric acid, followed by extraction with a mixed solvent of ethyl acetate and tetrahydrofuran (1:2 by volume). The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether and collected by filtration to obtain 7-[2-(5-formamido-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.75 g).
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].O[Li].O>O>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(F)cc1OCCCCCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCCOc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
Methanol (500 ml) and water (500 ml) were added to the crude reaction mixture obtained in Example 24. LiOH hydrate (1.4 mol) was added and the reaction mixture was stirred at room temperature for 16 h. Then, water (500 ml) was added and the organic solvent was evaporated under vacuum. The mixture was extracted with methyl tert-butyl ether to remove impurities. The water layer was adjusted to pH 8-9 and extracted again with ethyl acetate (3×500 ml). The water layer was adjusted to pH 4-5 and ethyl acetate was added. The organic layer was separated, washed with brine, dried and concentrated in vacuo. Yield: 120 g (purity 80%, 75% yield over 2 steps).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:29][CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: Cc1nc2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: BrCc1nc2ccccc2o1
Yield: 37 %

Procedure:
509.8 mg of dibenzoyl peroxide were added to a solution of 56 ml of 2-methylbenzoxazole and 18.73 g of N-bromosuccinimide in 20 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 6 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude crystalline solid. This was dissolved in ethyl acetate and then washed consecutively with a saturated aqueous sodium sulfite solution, water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude residue which was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate to give 3.34 g (yield 37%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([F:22])[CH:9]=2)=[N:6][CH:7]=1.[Na+].[CH3:24][S:25]([O-:27])=[O:26].[OH-].[Na+].O>CS(C)=O>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(F)c2)nc1
Yield: 33.6 %

Procedure:
2-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-5-(methylsulfonyl)pyridine (0.168 g, 34%) was prepared as a white solid from 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine (0.50 g, 1.40 mmol), methanesulfinic acid sodium salt (0.72 g, 80%, 5.58 mmol) Cul (0.80 g, 4.19 mmol), NaOH (67 mg, 1.68 mmol) and water (0.4 mL) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was triturated with hot MeOH containing 5% of CHCl3. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J=2.4 Hz), 8.22 (dd, 1H, Ja=8.3 Hz, Jb=2.5 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.90-7.70 (m, 2H), 7.50-7.30 (m, 5H), 7.11 (t, 1H, J=8.6 Hz), 5.23 (s, 2H), 3.13 (s, 3H); LRMS (ESI), m/z 358 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=2)=[O:12])[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH:15]=2)=[O:12])[CH:5]=[CH:6][N:7]=1
Reactant: NCc1cccc(NC(=O)c2nc(C3CC3)n3ccnc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nccn2c(C3CC3)nc(C(=O)Nc3cccc(CNS(=O)(=O)c4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 68A (0.102 g) in DMF 3 mL was treated with triethylamine (0.112 ml, 0.800 mmol) and benzenesulfonyl chloride (0.026 ml, 0.200 mmol), stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), concentrated to dryness and purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.29 (m, 4H) 2.34-2.58 (m, 1H) 3.98 (d, J=5.95 Hz, 2H) 7.04 (d, J=7.54 Hz, 1H) 7.19-7.36 (m, 2H) 7.48-7.69 (m, 4H) 7.72 (s, 1H) 7.77-7.91 (m, 2H) 7.98 (d, J=5.55 Hz, 1H) 8.18 (t, J=6.35 Hz, 1H) 9.08 (s, 1H) 10.32 (s, 1H) 10.69 (s, 1H). MS (ESI(+)) m/e 463 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[C:54]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=4[C:48]4[C:43]3=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:40]2[CH:41]=[CH:36][CH:37]=[C:38]([N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=4[C:49]4[C:54]3=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:39]=2)[CH:5]=[C:4]([Si:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
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: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (4.02 g, 8.12 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (1.500 g, 4.06 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol), K2CO3 (1.123 g, 8.12 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen for 24 h. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (9/1 to 4/1, v/v) as eluent and recrystallized from hexane/DCM (9/1, v/v) to yield 9-(3′-Bromo-5′-(triphenylsilyl)-[1,1′-biphenyl]-3-yl)-9H-carbazole (2.1 g, 79%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([SH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[OH-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][Cl:23]>C(O)C>[ClH:23].[F:1][C:2]1[C:7]([S:8][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: ClCc1ccccn1
Reactant: Fc1c(F)c(F)c(S)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(SCc2ccccn2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
Pentafluorothiophenol (5 g) was added to a solution of sodium hydroxide (2.0 g) in ethanol (50 ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.1 g) in ethanol (25 ml). The mixture was stirred at ambient temperature for 4 hours, filtered through Kieselghur and the solvent removed by evaporation. The residue was converted into the hydrochloride with ethereal HCl solution and this was recrystallised from acetone-ether to give 2-(((pentafluorophenyl)thio)methyl)pyridine, hydrochloride (5.0 g) mp 157°-8° C. (Found: C,44.0; H,2.4; N,4.0; C12H6F5NS.HCl requires C,44.0; H,2.15; N,4.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C

Procedure:
41.1 g (0.3 mol) of p-aminobenzoic acid and 300 ME of acetic acid were put into a 250 Ml flask, dissolved, and then 29.4 g (0.3 mol) of maleic acid anhydride was slowly added at 10° C. to obtain a yellow precipitate. This yellow precipitate was recrystallized using a mixed solution of DMF and ethanol (50:50, w/w). The recrystallized intermediate was treated at 85° C. for 15 minutes using sodium acetate and acetic acid anhydride, cooled to room temperature, and then precipitated using an ice water bath to obtain a precipitate. The obtained precipitate was recrystallized using a mixed solution of ethyl acetate and n-hexane (50:50, w/w) to obtain N-(p-carboxyphenyl) maleimide.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])C)C.ON1C2C=CC=CC=2N=N1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[N:39]=2)=[CH:34]\[C:35](O)=[O:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].N1CCCCC1>CN(C)C=O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30](/[C:33](/[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[N:39]=2)=[CH:34]\[C:35]([N:10]2[CH2:9][CH2:8][CH2:7][CH2:12]2)=[O:36])=[CH:31][CH:32]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/C(=O)N2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reaction time: 0.25 h
Yield: 40 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg) and 1-hydroxybenzotriazole (61 mg) were added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-enoic acid obtained in Reference Example 4-6 (137 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 15 minutes. Thereafter, piperidine (50 mg) was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate. This was sequentially washed with saturated aqueous sodium bicarbonate, water and brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one as a colorless oil (63 mg, 40%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[S:13]1C=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[NH:11][C:10]1[C:5]2[N:6]([CH:2]=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CNc1nccn2c(Br)cnc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1csc(Nc2nccn3ccnc23)c1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a solution of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (50 mg, 0.2 mmol) in tetrahydrofuran (2 ml) under nitrogen was added 2-thiopheneboronic acid (41 mg, 0.3 mmol), K2CO3 (1.1 ml of a 1 M solution in water) and 16 mg (0.1 mmol) of PdCl2(Dppf)CH2Cl2 (16 mg, 0.1 eq). The mixture was heated at 70° C. in a sealed tube overnight. The product was precipitated by adding methanol. The filtrate was evaporated and purified by preparative thin layer chromatography on silica gel to give additional title compound for a total of 45 mg (100% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH:28]([CH3:36])[CH2:29][CH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([NH:27][CH:28]([CH3:36])[CH2:29][CH2:30][CH2:31][C:32]([OH:34])([CH3:35])[CH3:33])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Reactant: CC(N)CCCC(C)(C)O
Product: CC(CCCC(C)(C)O)Nc1nc(N2CCS(=O)CC2)c2ncnc(NCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 3 from 8-benzylamino-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 232°-233° C.) and 6-amino2-methyl-2-heptanol. Resin.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[S:15]1[CH:19]=[CH:18][N:17]2[CH:20]=[N:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.ClCCl>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[C:19]1[S:15][C:16]2=[C:22]([C:23]([O:25][CH3:26])=[O:24])[N:21]=[CH:20][N:17]2[CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)OC)c2s1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A solution (5 ml) of 0.716 g of tri-n-butylstannyl Chloride in THF was added to a solution (20 ml) of 0.364 g of methyl imidazo[5,1-b]thiazole-7-carboxylate in THF at −70° C. A 1.0 N lithiumbis(trimethylsilyl)amide/n-hexane solution (4.4 ml) was added dropwise thereto at −70° C. The mixture was stirred at −50° C. for 30 min. The reaction solution was added to an ice cold mixed solution composed of 50 ml of 0.2 N phosphate buffer (ph 7) and 50 ml of dichloromethane with stirring. The organic layer was separated, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was subjected to separation and purification by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 0.395 g of the title, compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][C@@H](C)CSC)[O:5][C:6]2=[O:11].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CC1C=CC([NH2:28])=C(C)C=1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH2:28])(=[O:11])[C:7]1[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:12])=[O:5]
Reactant: CSC[C@H](C)N=C1OC(=O)c2cccc(Cl)c21
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
4-Chloro-3-[(S)-1-methyl-2-methylthioethylimino]-3-H-isobenzofuran-1-one (0.2 g) and 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylaniline (0.22 g) were dissolved in acetonitrile (10 ml), to which p-toluenesulfonic acid hydrate (0.01 g) was added, and then stirred at room temperature for three hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-chloro-N2-(S)-1-methyl-2-methylthioethyl)phthalamide (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:31])=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
35 (152 g, 0.45 mol, 1 equiv.) was suspended in dichloromethane (1.5 L) and dimethylformamide (1 mL) was added. Oxalyl chloride (71.6 g, 0.56 mol, 1.2 equiv.) was added drop-wise over 30 minutes at 0° C. After addition, the cold bath was removed and the reaction mixture was further stirred at room temperature for 3.5 h. The solvent and any unreacted oxalyl chloride were evaporated to yield a white solid, which was further dried on a rotary evaporator under vacuum at 40° C. overnight to yield dry 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoyl chloride 36 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.97 (s, 1H), 8.71 (d, 1H), 7.91 (dd, 1H), 7.60 (d, 1H), 7.57 (dd, 1H), 7.47 (dd, 1H), 7.21-7.15 (m, 1H), 3.99 (s, 3H). MS (ES) m/z 339.9 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])(=O)C.[Cs+].CS(C)=O>C(OCC)(=O)C.[Cu]>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:9][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([NH2:23])=[N:13]2)[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Reactant: N#Cc1cccnc1Cl
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2nc(N)c3cccnc32)C1
Temperature: 100 °C

Procedure:
Tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4 g, 19.87 mmol), 2-chloro-3-cyanopyridine (3 g, 21.65 mmol), cesium acetate (14 g, 72.9 mmol), and copper powder (0.126 g, 1.987 mmol) were placed under nitrogen. Dry dimethylsulfoxide (20 mL) was added and the mixture stirred at 100° C. After 1 hour the mixture was cooled and diluted with ethyl acetate (300 mL). The mixture was filtered through a pad of celite and the filtrate washed with 10% saturated sodium bicarbonate (500 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (10% (2 N ammonia in methanol) in dichloromethane) gave the desired tert-butyl(trans-3-(3-amino-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (2.72 g, 8.97 mmol, 45.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH:10]=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH2:10][NH:15][CH3:14])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cc1c(C=O)sc2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-chloro-3-methyl-benzo[b]thiophene-2-carbaldehyde (5.10 g, 24.2 mmol) was added a solution of 2 M methylamine in methanol (81 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (81 mL). The solution was cooled to 0° C., NaBH4 (1.37 g, 36.3 mmol) was added in one portion, and stirring was continued overnight. The mixture was concentrated under reduced pressure and the residue was combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to the title compound (4.83 g, 88%) as a pale yellow oil which crystallized under vacuum: 1H NMR (300 MHz, CDCl3) δ 7.69-7.59 (m, 2H), 7.25 (m, 1H), 3.96 (s, 2H), 2.50 (s, 3H), 2.31 (s, 3H).