Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Reactant: c1nc[nH]n1
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:32][CH:33]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=O)C1C=CC=CC=1>O>[CH:33]1([NH:32][C:28]2[N:27]=[CH:26][N:25]=[C:24]3[C:29]=2[N:30]=[CH:31][N:23]3[CH:13]2[O:12][C@H:11]([CH2:10][OH:9])[C:15]([CH3:16])([OH:17])[C@:14]2([F:22])[CH3:21])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Solvent: O
Product: CC1(O)[C@@H](CO)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Yield: 78.6 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(6-(cycloheptylamino)-9H-purin-9-yl)-4-fluoro-3,4-dimethyltetrahydrofuran-2-yl)methyl benzoate (about 0.3 g, 0.55 mmol) in methanolicammonia (25% w/w 10 ml) was stirred at room temperature for overnight. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 25% ethyl acetate in hexane as eluent furnished title compound (0.17 g) as a colorless solid. Yield: 78%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.34 (s, 1H), 7.95 (d, 1H, J=3.6 Hz), 6.59 (d, 1H, J=22.5 Hz), 5.80 (bs, 1H), 5.24 (s, 1H), 4.28-4.20 (m, 4H), 2.14-2.09 (m, 1H), 1.59-1.25 (m, 18H); ES Mass: [M+1]+ 394 (100%), 395 (30%); IR cm−: 3364, 2928, 2855, 2358, 1758, 1618, 1378, 1101, 844, 750; HPLC: 98.16%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH3:14][CH:13]([O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:15]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC(C)C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 103.6 %

Procedure:
To a solution of methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate (25 g) in DMF (250 mL) was added anhydrous potassium carbonate (297 mmol), and benzyl bromide (143 mmol). The mixture was stirred at 60° C. for 5 hours, then cooled to room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organics were combined and washed with further water, brine, dried (MgSO4) and concentrated in vacuo to give the desired compound (37 g) which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:6][N:7]([Si](C(C)C)(C(C)C)C(C)C)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CSc1cccc2c1c(Cc1ccc(Cl)cc1)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc2[nH]cc(Cc3ccc(Cl)cc3)c12
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 56.6 %

Procedure:
To a solution of the indole of Step 5 (1.9 g, 4.3 mmol) in THF (20 ml at 0° C. was added 1M TBAF (7 mL, 6 mmol). The reaction mixture was stirred for 1 minutes at 0° C. and water was added. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were dried over MgSO and concentrated The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 700 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.ICI.[CH3:16][C:17](=[CH2:25])[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCCCCC.ClCCl>[CH3:25][C:17]1([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:1][CH2:16]1
Reactant: CC[Zn]CC
Reactant: C=C(C)CCC(=O)OCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: ICI
Product: CCOC(=O)CCC1(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl zinc (31 mL of a 1.0 M solution in hexane, 31 mmol) in dry dichloromethane (100 mL) at 0° C. under an inert atmosphere was added TFA (2.4 mL, 31 mmol) in dichloromethane (5 mL) dropwise over a period of 30 min. To this suspension was added diiodomethane (2.5 mL, 31 mmol) in dichloromethane (5 mL) dropwise over a period of 10 min. The resulting solution was stirred at 0° C. for 30 min, at which time ethyl 4-methyl-4-pentenoate (2.0 g, 14 mmol) was added. The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (50 mL). The organic layer was separated and washed with water (50 mL), dried (MgSO4), filtered, and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography using 5% EtOAc-hexanes as eluant to give ethyl 3-(1-methyl-cyclopropyl)propanoate as a colorless liquid. TLC Rf=0.5 (5% EtOAc-hexanes); HPLC RT=3.43 min (Method A); 1H NMR 400 MHz, CDCl3, 4.12 ppm (q, J=8 Hz, 2H), 2.38 ppm (t, J=8 Hz, 2H), 1.57 ppm (t, J=8 Hz, 2H), 1.26 ppm, (t, J=8 Hz, 3H), 1.02 ppm (s, 3H), 0.28 ppm (m, 2H), 0.25 ppm (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([O:29][CH2:30][C:31](OC(C)(C)C)=[O:32])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:26][C@H:27]([O:29][CH2:30][CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](OCCO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-tert-Butyl ({3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}oxy)acetate (0.4 mmol, 200 mg) was dissolved in THF (2 mL) and charged with LiAlH4 (4 mmol, 4 mL, 1 M in THF) at −78° C., and stirred under rt for 1 h before the reaction mixture was heated to 50° C. for 16 h. Mixture was charged with EtOAc and allowed to stir at rt for 10 min, followed by an addition of Na2SO4.10H2O. The reaction mixture was passed through a pad of Celite and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 1-3% MeOH in DCM), yielding the title compound as a colorless oil; NMR 1H NMR (400 MHz, CD3OD) δ 7.47(td, 2H), 7.43-7.42 (m, 1H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.19 (td, J=1.2 Hz, 8 Hz, 1H), 7.13 (dd, J=2.4 Hz, 8.0 Hz, 1H), 6.98 (d, J=4.8 Hz, 1H), 5.17 (s, 2H), 4.16 (p, J=7.2 Hz, 1H), 3.66-3.65 (m, 2H), 3.51 (t, J=2.4 Hz, 2H), 3.50-3.43 (m, 1H), 2.88-2.81 (m, 2H), 2.46-2.38 (m, 2H). MS (ES+): m/z 431 (100) [MH+].
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (20 mL), L-proline (0.013 g, 0.11 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.14 g, y. 40%).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH2:9][Cl:10].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+]>>[Cl:10][CH2:9][CH2:8][CH2:7][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: ClCCCBr
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Product: CC(C)(C#N)CCCCl
Temperature: 69 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Isobutyronitrile (13.8 g, 0.20 mole), and 1-bromo-3-chloropropane (34.5 g, 0.22) are added sequentially to a stirred 1 M solution of lithium bis(trimethylsilylamide) (200 ml, 0.20 mole) in hexanes, stirred for two hours at 69° C. and quenched with water. The phases are separated and the organic phase is concentrated in vacuo to afford the title product as an oil, 38.9 g (64% pure, 85.7% yield), identified via gas chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(O)c2)CC1
Yield: 75 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:20][C:19]=3[N:37]([CH3:45])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:48].O1CCOCC1>>[ClH:48].[ClH:48].[CH3:45][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:46]=[CH:47][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccc3N3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of t-Butyl N-{2-[4-(2,4-dioxothiazolidine 5-ylmethyl)phenoxyacetylamino]-5-[2-(piperidin-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.80 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 19 hours. The solvent of the reaction mixture was evaporated to dryness. Ethyl acetate was added to the residue and insoluble product was collected by filtration and subjected to reversed-phase high performance liquid chromatography using acetonitrile/water=1/1 as the eluant and then treated with 4N hydrogen chloride/ethyl acetate to give the title compound (0.47 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:32]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:35]=2[F:41])=[C:31]([CH3:42])[C:30](=[O:43])[N:29]([CH3:44])[CH:28]=1)=O)#[N:21].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:63]=[N+:64]=[N-:65])(C)(C)C>CC#N.C(OCC)(=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:32]2[C:27]([C:25]3[N:24]([CH2:23][CH2:22][C:20]#[N:21])[N:65]=[N:64][N:63]=3)=[CH:28][N:29]([CH3:44])[C:30](=[O:43])[C:31]=2[CH3:42])=[C:35]([F:41])[CH:36]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NCCC#N)cn(C)c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Reaction time: 22 h
Yield: 61 %

Procedure:
PPh3 (83 mg, 0.32 mmol) was added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-cyano-ethyl)-amide (51 mg, 0.12 mmol) in MeCN (1.5 mL). DIAD (0.065 mL, 0.31 mmol) and TMSN3 (0.045 mL, 0.32) were added dropwise. After 22 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave clean desired product (33 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CCOC(C)=O.O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(N3CCN(c4nc5ccccc5[nH]4)CC3)ccnc2c1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (247 mg, 1.0 mmol) and 2-chlorobenzimidazole (46 mg, 0.3 mmol) are heated at 150° C. for 1 h. The mixture is dissolved in EtOAc-water. The organic layer is separated, dried (MgSO4), and concentrated. Column chromatography of the residue with hexane-EtOAc furnishes the title product as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:33]([O-])=O.[CH:36](O)=O>[Pd]>[NH:1]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N:33]=[CH:36]1
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=CO
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Prepared from N-[1-((4-amino-3-nitro-phenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-naphthalene-2sulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: C([CH:5]1[CH:8](OC2C=CC=CC=2)[N:7]([C:16]2[S:17][CH:18]=[C:19]([C:21](=[O:62])[NH:22][CH:23]([CH2:43][O:44][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:24][O:25][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=2)[CH:6]1OC1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:88]1CCCC1>>[OH:88][CH:5]1[CH2:6][N:7]([C:16]2[S:17][CH:18]=[C:19]([C:21](=[O:62])[NH:22][CH:23]([CH2:24][OH:25])[CH2:43][OH:44])[N:20]=2)[CH2:8]1
Reactant: C1CCOC1
Reactant: CC(C)(C)C1C(Oc2ccccc2)N(c2nc(C(=O)NC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cs2)C1Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NC(CO)CO)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 3-t-butyldiphenyloxy-1-{4-[2-(t-butyldiphenylsilyloxy)-1-(t-butyldiphenylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (3.19 g, 3.23 mmol) (obtained as described in Reference Example 39(3)) in anhydrous tetrahydrofuran (160 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (11.6 ml, 11.6 mmol) in an ice bath. The mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (9:1→8:2) as the eluant to afford 3-hydroxy-1-{4-[2-hydroxy-1-(hydroxymethyl)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.21 g, yield 100%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2c(F)cccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a solution of 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.74 g, 3.60 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (1.64 g, 14.4 mmol) and triethylsilane (1.68 g, 14.4 mL). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with a gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.54 g, 92%) as a colourless solid: mp 115-118° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.42-7.26 (m, 11H), 7.01 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.91 (s, 1H), 6.67 (dd, J=8.8, 8.8 Hz, 1H), 6.27 (s, 1H), 6.23 (d, J=7.9 Hz, 1H), 4.99 (s, 1H), 4.20-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.2, 157.9 (d, 1JC-F=248 Hz), 147.1, 145.0 (d, 3JC-F=8.7 Hz), 142.7, 137.7 (d, 2JC-F=30.9 Hz), 135.4, 130.1 (d, 3JC-F=8.7 Hz), 128.4 (d, 3JC-F=13.9 Hz), 128.3 (d, 3JC-F=8.4 Hz), 127.5 (d, 3JC-F=11.9 Hz), 119.4, 117.9 (d, 2JC-F=18.9 Hz), 116.1, 109.3 (d, 2JC-F=20.3 Hz), 107.2 (d, 4JC-F=2.1 Hz), 103.1, 73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 467.9 (M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[C:20]([Br:21])=[CH:19][N:18]([CH3:22])[N:17]=2)[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:21][C:20]1[C:16]([C:12]2[CH:11]=[C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:15]=[CH:14][CH:13]=2)=[N:17][N:18]([CH3:22])[CH:19]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3cccs3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To thiophene-2-carbonyl chloride (11 μL, 0.09 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg, 0.09 mmol) and triethylamine (14 μL, 0.09 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (24 mg, 68%), m.p. 127.8-128.6° C. (EtOAc/hexane).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.[CH3:21][NH2:22]>C1COCC1.O>[I:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:4]1[N:3]=[C:2]([NH:22][CH3:21])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:11]
Reactant: CN
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 85 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
A mixture of compound 6 (25 mg, 0.06 mmol) and 2M methylamine in THF (1 mL) and 40% methylamine in water (1 mL) was stirred for 14 h at 85° C. After removal of volatiles in vacuo, the residue was triturated with methanol-water, and the solid that formed was collected by suction filtration, washed with water (10 mL), and dried to give compound 11 (22 mg, 89.0%). 1H NMR (DMSO-d6) δ 2.76 (d, J=4.6 Hz, 3 H, NHCH3), 3.55 (s, 3 H, 9-CH3), 4.59 (br s, 2 H, CH2), 6.28 (br d, J=4.3 Hz, 1 H, exchangeable with D2O, NHCH3), 7.10 (pseudo t, J=7.9 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.6 Hz, 1 H, H-17), 7.57 (d, J=7.6 Hz, 1 H, H-15), 7.67 (s, 1 H, H-13), 7.35 (s, 1 H, H-8), 7.83 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:15])=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[O:5][C:4]1=[O:16])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:12][C:10]1[CH:9]=[C:8]([F:15])[C:7]2[N:3]([CH2:1][CH3:2])[C:4](=[O:16])[O:5][C:6]=2[CH:11]=1
Reactant: CCn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)oc2cc(N)cc(F)c21

Procedure:
Prepared from 3-ethyl-4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 1, 1.05 g, 4.90 mmol), ammonium chloride (2.62 g, 49 mmol) and iron powder (1.09 g, 19.6 mmol) in ethanol (30 ml) and water (15 ml) according to the method of EXAMPLE 86, Step 7 (0.95 g, 99%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15].[OH-].[K+]>C(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:15][C:14]1[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 26.1 %

Procedure:
To a solution of 15.0 g (70.1 mm) of 2-chloromethylquinoline hydrochloride and 7.71 g (70.1 mm) of resorcinol in 50 ml ethanol under nitrogen is added over 30 minutes dropwise a solution of 9.1 g (140.0 mm) potassium hydroxide in 50 ml ethanol. After addition is complete the reaction mixture is refluxed for 2 hours. The solution is allowed to come to room temperature; the precipitate is then filtered off. The mother liquor is evaporated and the residue is triturated with methylene chloride. Evaporation of the organic solvent gives 10.0 g of crude product. HPLC purification affords 4.6 g of a white solid which when recrystallized from toluene affords white crystals, m.p. 153°-155° C.
Reaction SMILES: C[Si](C)(C)[Cl:3].C([O:8][C:9]1([CH3:24])O[CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[O:10]1)C>C(Cl)Cl>[C:9]([O:10][CH:11]([CH2:12][Cl:3])[CH2:14][O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(=[O:8])[CH3:24]
Reactant: CCOC1(C)OCC(COc2ncccc2OC)O1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1cccnc1OCC(CCl)OC(C)=O
Reaction time: 1 h

Procedure:
45 ml of trimethylchlorosilane are added to a mixture of 85 g of 2-ethoxy-5-(3-methoxy-2-pyridyloxymethyl)-2-methyl-1,3-dioxolane in 500 ml of methylene chloride and the mixture is stirred for one hour at 20°-30°. Complete evaporation under reduced pressure yields crude 2-(2-acetoxy-3-chloro-propoxy)-3-methoxy-pyridine in the form of an oil, which is used without purification.