Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36]N>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=466.1 (M+H)+
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1([CH3:31])[CH2:16][CH2:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:13][CH2:12]1>C1COCC1>[CH3:10][C:11]1([CH3:31])[CH2:16][CH2:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:13][CH2:12]1
Reactant: CC1(C)CC=C(Oc2ccc(-c3cccnc3N)cc2)CC1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 382 mg) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (0.402 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-((4,4-dimethylcyclohex-1-en-1-yl)oxy)phenyl)pyridin-2-amine (563 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 3 hr. The mixture was quenched with water at 0° C. Water and EtOAc were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give the title compound (369 mg) as a pale yellow solid. A part of the product was crystallized from MeCN/IPE to give a pale yellow crystal.
Reaction SMILES: [Br:1]Br.[CH2:3]([C@@:7]12[C@H:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[CH:17]=[C:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[CH2:15]2)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:17]1[C:18](=[O:23])[C@@H:19]([CH2:20][CH2:21][CH3:22])[C@@:7]2([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][C:14]3[CH:13]=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[C:8]=12
Reactant: CCCC[C@]12Cc3cc(O)ccc3C1=CC(=O)[C@H]2CCC
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC[C@]12Cc3cc(O)ccc3C1=C(Br)C(=O)[C@H]2CCC
Temperature: 2.5 °C
Reaction time: 1.17 h

Procedure:
Bromine (0.0072 mL, 0.14 mmol) was added to an ice-cold mixture of (rac)-(1S,8aR)-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (40 mg, 0.14 mmol) and NaHCO3 (59 mg, 0.70 mmol) in CCl4 (0.48 mL). The resulting mixture was sonicated for 20 seconds and then stirred at 0-5° C. for 70 minutes. The mixture was diluted with CH2Cl2 (30 mL) and washed with water (30 mL), and the aqueous phase was back-extracted with CH2Cl2 (2×10 mL). The combined organics were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 10:1 hexane-EtOAc, to give a clear oil. This material was further purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing twice with 5:1 hexane-EtOAc. The major UV visible band provided (rac)-(1S,8aR)-3-bromo-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].C=O.[BH3-][C:42]#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:32][CH2:31][N:30]([CH3:42])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(pyrrolidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in methanol was added formalin (5 equiv.) stirred it at room temperature for 10 min. Then NaBH3CN (1 equiv.) was added to it Resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (30% yield). LCMS: 532.35 (M+1)+; HPLC: 89.75% (@ 254 nm) (Rt; 7.188); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.84 (bs, 1H), 8.30 (s, 1H), 7.84 (d, 1H, J=10 Hz), 6.91 (bs, 1H), 5.89 (s, 1H), 5.21 (m, 1H), 4.38 (d, 2H, J=4.4 Hz), 4.29 (bs, 1H), 4.21 (bs, 1H), 3.70 (bs, 2H), 2.76 (m, 2H), 2.66 (bs, 1H), 2.43 (m, 1H), 2.32 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 2.00-1.94 (m, 4H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 82 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.06 g, 0.1 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.06 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as an off-white solid; mp 132–135° C.; MS (ESI) m/z 729.74 ((M−H)−); HRMS: calcd for C39H33Cl2FN2O5S, 730.1471; found (ESI+), 731.15514.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1>CC(O)C.C([O-])(=O)C.[NH2+]1CCCCC1>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (549 mg) in 2-propanol (5 mL) were added a solution of 4-[(trans-2-hydroxycyclohexyl)amino]thiazol-2(5H)-one (520 mg) in 2-propanol (5 mL) and piperidinium acetate (240 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (557 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>CO.N1C=CC=CC=1>[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1/[C:30](=[N:2]/[OH:3])/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@@H]1CN2c3c(cc(C(=O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc(/C(=N/O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C

Procedure:
Hydroxylamine hydrochloride (77 mg, 0.001 mmol) was added to a solution of (2R,4S,4aS)-rel-9,10-difluoro-2,4-dimethyl-8-(phenylcarbonyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 13, 280 mg, 0.6 mmol) in methanol:pyridine (1:1, 3 mL) and the solution was heated to 90° C. for 12 hours. Solvents were removed and the residue was subjected to silica gel column chromatography using a gradient of ethyl acetate in pet. ether to give the title compound as a racemic mixture. Yield: 120 mg (42%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[CH3:20][C:21]([S:24]([N:26]=[C:27]1[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([S:24]([NH:26][C:27]1([CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH2:30][O:29][CH2:28]1)=[O:25])([CH3:20])([CH3:22])[CH3:23]
Reactant: CCOC(=O)CC
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N-diisopropylamine (78 g, 770 mmol) was dissolved in anhydrous THF (200 mL) and cooled to −78° C. under nitrogen. Butyl lithium (2.5M solution in hexane, 297 mL, 743 mmol) was added drop-wise. The reaction was removed from the cooling bath for 30 minutes, then re-cooled to −78° C. A solution of ethyl propionate (72.8 g, 713 mmol) in anhydrous THF (200 mL) was added drop-wise and the reaction allowed to stir at room temperature for 1 hour. The reaction was cooled to −78° C. once again and a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Preparation 39, 50 g, 285 mmol) in anhydrous THF (200 mL) was added drop-wise. The reaction was stirred at between −40° C. and −60° C. for 4 hours before being quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate elution) was not successful. The title compound was obtained as a yellow oil (40 g, 51% yield) and used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+].O>[Fe].C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CC(=O)CCC2
Yield: 89.6 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (0.20 g), iron powder (218 mg), ammonium chloride (52 mg), water (1.2 ml) and ethanol (4 ml) was refluxed for 2 hours. After cooling, the insoluble material was filtered off and the filtrate was evaporated in vacuo. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (153 mg).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[NH:4][C:5]([CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:3](=[O:14])[NH:4][C:5]([CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)[nH]c(=O)c1OCc1ccccc1
Temperature: 4 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-hydroxy-4-ethoxycarbonyl-6-methyl-2-pyridinone (prepared by the method of Feist et al., Chem. Ber., 1902, vol. 35, p. 1545; 23.9 g, 121 mmol) and benzyl bromide (14.4 mL, 121 mmol) in DMF (400 mL) at 0° C. was added cesium carbonate (39.7, 121 mmol). The resulting mixture was stirred at 4° C. for 48 h. More benzyl bromide was added (2.8 mL, 24 mmol) and the mixture was stirred at 4° C. for another 72 h. The solvent was removed in vacuo and the residue was suspended in CH2Cl2. The solids were removed by filtration and the filtrate solvent was removed in vacuo. The residue was purified by flash column chromatography using 1:3 EtOAc:hexanes as eluant to give the title compound (18 g; HPLC RT=15.04 min, method B).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C@@H:25]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:26].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:26][C@@H:25]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:24])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CBr)NC(=O)OCc1ccccc1
Reactant: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1)NC(=O)OCc1ccccc1

Procedure:
6-(4-Benzyloxyphenoxy)pyridin-3-ol (250 mg, 0.85 mmol) and benzyl ((S)-2-bromo-1-methylethyl)carbamate (232 mg, 0.85 mmol) were reacted with sodium hydride in DMF in analogy to example 1a. Yield: 118 mg (29%), M+H+: 485.11.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][CH2:9]/[CH:10]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
A mixture of 2-(tert-butyldimethylsilyloxy)acetaldehyde (54.64 mL, 258.2 mmol) in DCM (500 mL) was treated with (S)-2-methylpropane-2-sulfinamide (34.42 g, 284.0 mmol), followed by copper sulfate (103.0 g, 645.4 mmol) at ambient temperature. After stirring for 48 hours, the mixture was filtered through Celite and washed with DCM. The mixture was concentrated and purified on silica gel (10-30% EtOAc in hexane) to provide (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (67.3 g, 94% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=2.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>>[C:15]([C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Reactant: CC(C)C(=O)Cl
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(C)[nH]c2c1

Procedure:
Methyl 3-isobutyryl-2-methylindole-6-carboxylate (142 mg) was prepared from methyl 2-methylindole-6-carboxylate (305 mg) and isobutyryl chloride (0.47 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:33]([OH:34])[C@@H:14]2[O:15][Si:16]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:17][Si:18]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:19][CH2:20][C@H:13]2[CH2:12]1.[CH:35]1[CH:40]=[CH:39][C:38]([O:41][C:42](Cl)=[S:43])=[CH:37][CH:36]=1>C(Cl)Cl>[C:42](=[S:43])([O:41][C:38]1[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1)[O:34][C@@H:33]1[C@@H:14]2[O:15][Si:16]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[O:17][Si:18]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[O:19][CH2:20][C@H:13]2[CH2:12][C@H:11]1[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](OC(=S)Oc3ccccc3)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol (0.762 g, 1.44 mmol) and N,N-dimethylaminopyridine (0.529 g, 4.34 mmol) in DCM (20 mL) was added phenyl chlorothionocarbonate (0.440 mL, 3.2 mmol) and the solution was stirred for 1 h. The reaction mixture was concentrated and the residue purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.851 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=O)(=[O:11])=[O:10].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[N:25][NH:26][C:27]([NH2:29])=[S:28])(=[O:11])=[O:10]
Reactant: NNC(N)=S
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Solvent: CCO
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NNC(N)=S)c1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy-]-propionaldehyde (472.5 mg, 1.35 mmol, as prepared in step d of example 8), thiosemicarbazide (124.5 mg, 1.37 mmol) and ethanol (4.5 mL) was refluxed for 2 hours. The solution was cooled to room temperature and approximately 3 mL ethanol was removed by rotary evaporation. The residual oil in ethanol was heated to 50° C. and the product crystallized. The title compound was isolated by filtration as a white solid (493 mg, 86%). 1H-NMR (300 MHz, DMSO-d6) δ 7.76 (ddd, 1H, J=1.8, 7.4, 8.4 Hz), 7.69 (dd, 1H, J=1.7, 7.9 Hz), 7.43 (t, 1H, J=4.8 Hz), 7.36 (d, 1H, J=8.4 Hz), 7.09 (ddd, 1H, J=0.9, 7.4, 7.8 Hz), 6.72 (br s, 1H), 6.48 (br s, 1H), 6.37 (t, 1H, J=2.3 Hz), 4.08 (t, 2H, J=6.5 Hz), 3.99 (s, 3H), 2.58 (q, 2H, J=6.4 Hz), 2.21 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H21N3O5S2 : 424.1 (M+H), 446.1 (M+Na). Found: 423.9, 445.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: C1CCN(CCC2CCNCC2)C1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 49.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (230 mg, 1.3 mmol) to afford the desired product (190 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 3.98-3.90 (m, 2H), 3.32-3.23 (m, 2H), 2.58-2.50 (m, 6H), 2.55 (s, 3H), 1.86-1.53 (m, 11H); ESI MS m/z 387 [M+H]+
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[N:30]1[CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH3:28])[N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:42][CH:43]=1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2C(C)CCCC2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline Rf value: 0.5 (RP 8, methanol/five percent saline solution=4:1) C31H33N3O3
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 15.00 g (138.7 mmol) of 1,4-phenylenediamine and 255 ml of tetrahydrofuran. A solution prepared by dissolving 9.07 g (92.5 mmol) of maleic anhydride in 45 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 3 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed with 30 ml of tetrahydrofuran, and dried at 40° C. to obtain 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as an orange powder. To 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 36 ml of water and the mixture was cooled to 0 to 10° C., and 17.59 ml of a 5N sodium hydroxide aqueous solution was dropped. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 270 ml of ethanol was added, and the mixture was stirred at 70° C. for 1 hour, cooled down to room temperature, then, the solid was filtrated and washed twice with 25 ml of methanol. The resultant solid was dried at 45° C. for 2 hours, to obtain 16.2 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate as a pale brown-white powder. Yield: 76.8%