Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of commercially available methyl (S)-mandelate (2.39 g, 14.4 mmol) in dichloromethane (50 mL) is added imidazole (1.18 g, 17.3 mmol), tert-butyldimethylsilyl chloride (2.38 g, 15.8 mmol) and 4-dimethylaminopyridine (176 mg, 1.44 mmol). The mixture is stirred for 16 hrs then diluted with ether, washed with water, brine, then dried (MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (25:75) gives 3.67 g of the product. 1H NMR (CDCl3) δ 7.45-7.40 (m, 2H), 7.35-7.25 (m, 3H), 5.20 (s, 1H), 3.65 (s, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H); MS: m/z 281 (M++1)
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:66]>C1COCC1>[ClH:66].[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:37]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:38]=3[N:39]=[CH:40][CH:41]=[N:42]4)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cccc2nccnc12
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)c2nccnc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline* (0.45 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (20 mL). The reaction was stirred at room temperature for 1.5 h and at 65° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (1:1) as eluent. The resulting solid was crystallized twice from diethyl ether/petroleum ether to remove PPh3O. The recrystallized material (0.50 g) was dissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection had occurred according to HPLC/MS). The mixture was concentrated and the residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h. After concentration in vacuo, the residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was lyophilized to give a yellow oil that was dissolved in 1 M HCl. The solution was concentrated and MeOH and diethyl ether was added. The precipitate formed was collected and dried in vacuum to give 0.32 g (76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting the stated structure. HRMS m/z calcd for C18H20N6O2 (M)+ 352.1648, found 352.1662.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[C:26]2=[N:27][CH:28]=[C:29]([C:31](O)=[O:32])[CH:30]=[C:25]2[N:24]=[CH:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31]([C:29]3[CH:30]=[C:25]4[N:24]=[CH:23][N:22]([CH3:21])[C:26]4=[N:27][CH:28]=3)=[O:32])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Cn1cnc2cc(C(=O)O)cnc21
Product: Cn1cnc2cc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cnc21

Procedure:
3-Methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 3-Methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid. MS calcd. for C24H19ClN5O2 [(M+H)+] 444.1, obsd. 444.0.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH2:31])[C:25]([OH:27])=[O:26].Cl>CN(C=O)C>[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:18](=[O:20])[CH2:17][CH2:16][NH:15][S:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)(=[O:13])=[O:14])[C:25]([OH:27])=[O:26]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CCCCCc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCc1ccc(S(=O)(=O)NCCC(=O)Nc2ccc(C(=O)O)cc2O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a solution of the product of Step 1 (200 mg, 0.67 mmol) in dry DMF (7 mL) was added 1,1-carbonyldiimidazole (CDI) (120 mg, 0.73 mmol). The resulting mixture was stirred at 40° C. for 1 h, then treated with 3-hydroxy-4-aminobenzoic acid (107 mg, 0.7 mmol). The mixture was stirred at 40° C. for 16 h, then poured into 1N aqueous HCl (100 mL). The resulting yellow precipitate was filtered, washed with diethyl ether, and azeotroped to dryness once from toluene to give the crude title compound (337 mg), which was used directly in the next step without further purification. MS m/e 434.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C:3](=[O:42])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:31]([C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]>CO.[Pd]>[CH3:1][C:2]([CH3:44])([CH3:43])[C:3](=[O:42])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1Cc2ccccc2C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1Cc2ccccc2C[C@H]1C(=O)O

Procedure:
A solution of the diester product from part (b) in methanol is added to a 10% palladium on carbon catalyst and the resulting mixture is shaken in a Parr hydrogenation apparatus for several hours. The catalyst is filtered off and the methanol stripped from the filtrate. The crude product is chromatographed on silica gel to yield (S)-1,2,3,4-tetrahydro-2-[[[(2,2-dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)-phosphinyl]acetyl]-3-isoquinolinecarboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([C:49]3[NH:53][N:52]=[CH:51][CH:50]=3)[CH:46]=[CH:47][CH:48]=2)O1.O1CCOCC1>CCOC(C)=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.O>[NH:53]1[C:49]([C:45]2[CH:44]=[C:43]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)=[C:18]([C:28]([NH:29][CH3:30])=[O:31])[C:17]=4[CH:32]=3)[CH:48]=[CH:47][CH:46]=2)=[CH:50][CH:51]=[N:52]1
Reactant: CC1(C)OB(c2cccc(-c3ccn[nH]3)c2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4ccn[nH]4)c3)cc12
Temperature: 90 °C
Yield: 94.8 %

Procedure:
Cesium carbonate (234 mg, 0.719 mmol) was added to Pd(Ph3P)4 (20.77 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (146 mg, 0.539 mmol). Dioxane (3 mL) and water (599 μL) was added at rt. The reaction was heated to 90° C. overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified by trituration with Et2O to give the titled compound (140 mg, 92%). 1H NMR (400 MHz, DMSO-d6) d ppm 13.40 (1H, br. s.), 12.91 (1H, br. s.), 8.45-8.55 (1H, m), 8.13 (1H, s), 7.97-8.08 (2H, m), 7.85-7.95 (1H, m), 7.73-7.85 (4H, m), 7.59-7.67 (1H, m), 7.49-7.58 (1H, m), 7.35-7.45 (2H, m), 6.84 (1H, br. s.), 2.87 (3H, d, J=4.52 Hz). LC-MS retention time: 1.41 min; m/z (MH+): 412. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=11.86 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=10.97 min, purity=99%.
Reaction SMILES: [OH-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:24])[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15]2)=[CH:10][CH:9]=1.C(C1OC1)Cl>O>[O:6]1[CH2:5][CH:3]1[CH2:4][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:24])[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)O
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCC1CO1
Solvent: O
Product: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Temperature: 70 °C

Procedure:
To a solution of 82.2 g (2.06 mol) of sodium hydroxide in 585 ml of water were added 3.7 liters of isopropanol and then 490 g (2.06 mole) of 7-hydroxyflavone. To the above mixture were then added 1645 ml (20.5 mole) of epichlorohydrin and the mixture heated at 70° C. for 2 hours with stirring. The hot reaction mixture was filtered to remove dimeric by-product. The filtrate was concentrated under reduced pressure (water aspirator) at 50°-60° C. The semisolid residue was treated with 4.4 liters of refluxing isopropanol and more of the dimer filtered from the hot mixture. The clear filtrate on cooling yielded a solid. This was filtered, washed with 600 ml of isopropanol and air dried; yield 434.3 g (72%) of a tan-colored product, mp 123°-130° C. (a pure sample melts at 133°-135° C. from i-PrOH). The crude epoxide was used for further reaction.
Reaction SMILES: C[C:2](C)=[O:3].[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[O:24][CH3:25])=[C:18]([CH3:27])[CH:17]=1.C=O>C(=O)([O-])[O-].[K+].[K+].O>[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:2][OH:3])[C:23](=[O:26])[O:24][CH3:25])=[C:18]([CH3:27])[CH:17]=1
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reactant: CC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Temperature: 30 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A mixture of 130 ml of acetone and 0.5 ml of water was added to a mixture of 10.01 g of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (prepared as described in Example 21(c) below) and 5.0 g of paraformaldehyde at room temperature. 0.30 g of potassium carbonate were added to the resulting mixture and the mixture was then stirred for 12 hours at 30° C. while subjected to ultrasonic irradiation. At the end of this time the reaction mixture was filtered and the solvent was removed from the filtrate by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel, using a gradient of dichloromethane and acetone as the eluent, gradually changing from a 9:1 by volume mixture of dichloromethane and acetone to a final 4:1 by volume mixture, to give 8.02 g (yield 73.4%) of the title compound as a solid having a melting point of 121°-123° C.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[OH:12][CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[NH2:4])[CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCNC1
Product: Nc1cc([N+](=O)[O-])ccc1N1CCC(O)C1
Yield: 46.6 %

Procedure:
According to a process similar to that described in Example II-1, starting from 3 g (19.22 mmol) of 2-fluoro-5-nitroaniline and 1.76 ml (21.14 mmol) of 3-hydroxypyrrolidine, 2 g of expected compound are obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)=[CH:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.ClCCl.CO>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: CN1CCNCC1
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 55.5 %

Procedure:
But using 0.98 g of 4-chloro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.21 g of potassium carbonate and 0.31 g of 1-methylpiperazine in 100 ml of acetonitrile. After flash chromatography on a silica column [eluent: dichloromethane/methanol (90/10 by volume)], 0.52 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of an oil, the characteristics of which are as follows:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].[Br:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:21][C:20]=1[CH2:33]Br.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:21][C:20]=1[CH2:33][C:14]([CH3:16])([CH3:15])[C:13]#[N:17]
Reactant: CC(C)C#N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C#N)Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.70 mL) in THF (15 mL) was added a 1.6 M solution of n-butyllithium in hexane (3.0 mL) at 0° C., and the mixture was stirred for 10 min. Isobutyronitrile (0.47 mL) was added at −78° C., and the mixture was stirred for 30 min. A solution of (4-bromo-3-(bromomethyl)phenoxy) (tert-butyl)dimethylsilane (1.00 g) in THF (5.0 mL) was added, and the mixture was stirred at −78° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (905 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH:16][C:17](=[NH:20])[S:18][CH3:19])=O)[N:7]=3.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:17]([S:18][CH3:19])[N:16]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CSC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CSc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1

Procedure:
1-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-2-methyl-isothiourea (27 mg, 0.068 mmol) was heated with isopropylhydrazine hydrochloride (23 mg, 0.20 mmol) in acetic acid (0.9 mL) at 100° C. overnight. The mixture was concentrated and the crude residue purified by reverse-phase HPLC to give 240. LCMS EI: 422.1
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:5][CH2:4]1)=[O:2].[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:21]\[C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:12]=1[CH2:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]1)(=[O:27])=[O:26]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C=O)CC1)CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C=O)CC1)CCCC3)C(=O)N2
Yield: 65.5 %

Procedure:
3-[3-(4-Formylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (61 mg, 0.2 mmol), prepared as described in Step 4 of Example 8, was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.2 mmol) following the procedure used in Example 1. Brown solid precipitated out and purified by flash chromatography, eluting with (dichloromethane: methanol 50/1,35/1,30/1) to give 67 mg of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2nc3ccccc3o2)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) and 2-chlorobenzoxazole (0.0573 ml) in DMF (1.4 mL) was added ethyldiisopropylamine (0.183 ml), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (175 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)=O>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1
Reactant: NC1=NC2(CO1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C=O
Solvent: CO
Product: NC1=N[C@@]2(CO1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12

Procedure:
2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (440 mg) was subjected to chromatography using 20:80:0.2 MeOH:CO2:DEA at 70 ml/min on a 20×150 mm, 5 m ChiralPak AD-H column and 100-bar system pressure. The first peak (RT=6.31 min) provided (4R)-2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (98% ee), and the second peak (RT=15.7 min) provided (4S)-2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (>99% ee).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:13][SnH:14]([CH3:16])[CH3:15]>O1CCCC1>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH2:2][Sn:14]([CH3:16])([CH3:15])[CH3:13])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: C[SnH](C)C
Reactant: C=CS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)CC[Sn](C)(C)C)cc1
Reaction time: 14.75 h
Yield: 73.2 %

Procedure:
The procedure described in Example 1 was employed except that 7.74 g (42.5 mmoles) of 4-tolyl vinyl sulfone, 7.0 g (42.5 mmoles) of trimethyltin hydride and 10 ml of tetrahydrofuran were the reactants and solvent. The irradiation proceeded for 14.75 hours. Evaporation of solvent afforded an oil which crystallized on standing. Recrystallization of the product from cold petroleum ether gave 10.8 g of 2-(p-tolylsulfonyl)ethyltrimethylstannane, m.p. 55.5°-58°C. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1310 cm-1, 1295 cm-1, 1260 cm-1, 1145 cm-1 (--SO2 --) and 750 cm-1 ((CH3)3Sn) employing a KBr disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: Cc1ccc(Nc2c(C)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)CCl)c2c(C)cccc2Cl)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
The solution of N-(2′-chloro-6′-methylphenyl)-4-methylaniline (1.4 g) in 2.21 g chloroacetylchloride is heated to 90° C. for 4 h. The mixture is diluted with toluene (25 ml), cooled to room temperature and washed with aqu. sodium carbonate. The organic phase is dried, evaporated and the residue is subjected to flash chromatography [57 g silica, toluene and toluene/ethylacetate (98:2)] to afford 1.45 g of N-(2′-Chloro-6′-methylphenyl)-N-chloroacetyl-4-methylaniline which is crystallised from heptane, mp: 113-114° C.