Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:38])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([C:35]([OH:37])=[O:36])[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[OH-].[K+:40]>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:38])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([C:35]([O-:37])=[O:36])[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[K+:40]
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C(=O)O)[nH]c(=O)c4c(O)c21)C3=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C(=O)[O-])[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.9 mg (13.3 μmol) Fredericamycin carboxylic acid (12) are dissolved in 5 mL DMF under nitrogen. At room temperature and under oxygen exclusion and vigorous stirring, 1.27 mL (12.7 μmol) of an aqueous 0.01 N KOH solution is added dropwise. It is stirred for 15 minutes at room temperature, and concentrated in high vacuum until dry.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][N:17](CC4C=CC(OC)=CC=4)[C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:31])[C:5]([NH:32][S:33]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)(=[O:35])=[O:34])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:31])[C:5]([NH:32][S:33]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)(=[O:35])=[O:34])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nc(OC)c3cc(NC(=O)c4c(Cl)ccc(NS(=O)(=O)CCCOc5ccc(OC)cc5)c4F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OCCCS(=O)(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc4[nH]nc(OC)c4c3)c2F)cc1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A 100 mL, round-bottomed flask was charged with 6-chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzamide (228.3 mg, 0.33 mmol) and TFA (0.5 mL). The reaction mixture was stirred at 80° C. until LC-MS showed that the starting material had been consumed (overnight). Then the CF3COOH was removed under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexane from 1/4 to 1/0, v/v) to afford 6-chloro-2-fluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzamide (181.4 mg, 96.38%). LRMS (APCI pos): >95% purity, 254 nm, m/e 564.1 and 566.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[C:38](=[O:39])[C:37]4[N:29]([C:30]5[C@H:31]6[CH2:40][C@@H:34]([C:35]=5[CH:36]=4)[CH2:33][CH2:32]6)[CH2:28][CH2:27]3)[C:21]=2[CH:41]=[O:42])=[CH:3]1.[BH4-].[Na+]>CO>[OH:42][CH2:41][C:21]1[C:22]([N:26]2[CH2:27][CH2:28][N:29]3[C:30]4[CH:31]5[CH2:40][CH:34]([C:35]=4[CH:36]=[C:37]3[C:38]2=[O:39])[CH2:33][CH2:32]5)=[N:23][CH:24]=[CH:25][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6[C@@H]6CC[C@H]7C6)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6C6CCC7C6)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of 170c (122 mg, 0.22 mmol) in methanol (20 mL) was added NaBH4 (24 mg, 0.64 mmol). The mixture was stirred at 20° C. for 2 h. The reaction was evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford the title compound (98 mg, 75%) as a white solid. MS-ESI: [M+H]+ 567.3. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 6.53 (s, 1H), 5.89 (s, 1H), 4.98 (t, J=5.0 Hz, 1H), 4.48-4.30 (m, 3H), 4.27-4.22 (m, 2H), 3.92-3.91 (m, 2H), 3.86-3.84 (m, 1H), 3.59 (s, 3H), 3.49-3.47 (m, 3H), 3.30-3.28 (m, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 1.87-1.76 (m, 3H), 1.61-1.59 (m, 1H), 1.09-0.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]=2[C:19]#[N:20])=[CH:4][CH:3]=1>[Ti](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:20][C:19]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[N:8]=[C:5]2[C:6]=1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4]2
Reactant: N#CC1=C(Nc2ccc(F)cc2)c2ccccc2CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc(F)cc13)-c1ccccc1CC2
Temperature: 140 °C

Procedure:
Under nitrogen, titanium tetrachloride (0.3 ml, 2.7 mmol) was added to the above enamine (Example 36) (0.65 g, 2.5 mmol) and the stirred mixture was heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxide (20 ml) was added and the mixture heated under reflux for 1 hour After being allowed to cool, this mixture was filtered and the solid washed with dichloromethane. Any organics in the filtrate were also extracted into dichloromethane. All extractions were combined, dried (Na2SO4), filtered and the solvent evaporated. Kugelrohr distillation (210° C., 0.07 mmHg) gave the product as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:14].CO>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([I:13])[CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH2:14]
Reactant: N
Reactant: Clc1cc(I)c2ncnc(Cl)c2c1
Solvent: CO
Product: Nc1ncnc2c(I)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4,6-dichloro-8-iodo-quinazoline (1.00 g, 3.08 mmol) was added 2.4 mL of 7N ammonia/methanol. The mixture was capped and shaken overnight at room temperature. The rxn was then concentrated via rotovap yielding product as a white solid. The product was purified by flash column (2.5-10% Methanol:Dichloromethane), yielding 450 mg of 6-chloro-8-iodo-quinazolin-4-amine 1H NMR (400 MHz, DMSO) δ 8.51-8.45 (s, 1H), 8.45-8.41 (d, J=2.0 Hz, 1H), 8.41-8.35 (d, J=1.9 Hz, 1H), 8.12-7.92 (bs, 2H). LCMS M/Z (M+H)=306.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][N:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: BrCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccco1
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a stirring suspension of 7-methylxanthine (2.54 g, 15.3 mmol) in dimethylsulfoxide (80 ml) was added sodium hydride (0.37 mg, 15.3 mmol) in one portion. After stirring for 30 minutes, freshly prepared furfuryl bromide (2.5 g, 15.3 mmol) was added next. After stirring at room temperature for 18 hours, the reaction was quenched by addition of water (150 ml). Saturated aqueous sodium chloride solution (30 ml) was added and the mixture was extracted with chloroform (4×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (3×50 ml), with saturated aqueous sodium chloride solution (2×50 ml) and dried over a mixture of sodium sulfate and activated charcoal. After filtration through a pad of celite, the solvent was evaporated under reduced pressure. The residue was treated with ethyl acetate. The solid was filtered, rinsed with cold ethyl acetate (2×25 ml) and vacuum dried to give 3-(2-furylmethyl)-7-methylxanthine (0.54 g, 1496 yield) as a beige solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>CN(C)C=O>[CH2:3]([N:12]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1c(NCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(CC(=O)c2ccccc2)Cc2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (42 mg of a 60% dispersion, 1.39 mmol) in dimethylformamide, place under nitrogen atmosphere and cool to -10°C. Add, by dropwise addition, a solution of 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.6 g, 1.26 mmol) in dimethylformamide. Stir at -10° C. for 30 minutes and add, by dropwise addition, benzyl bromide (0.24 g, 1.39 mmol).Stir for 5 hours, pour into 1N hydrochloric acid and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C(=O)O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-chloro-4-((4-methylpiperazin-1-yl)methyl)benzoate (270 mg, 0.96 mmol) in tetrahydrofuran was added to an aqueous sodium hydroxide solution (6 M, 1.5 mL) and the mixture was stirred at room temperature for 5 hours. The organic solvent was removed under reduced pressure and the residue was acidified with aqueous HCl until a white solid formed. The mixture was lyophilized to give a white solid (contained salt). LCMS (ESI): RT (min)=0.819, M+H+=268.8, method=B.
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C:6](O)=[C:4](O)[C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O:3][C@@H:2]2[CH:4]=[CH:6][C@H:8]3[CH2:10][O:11][C@@H:1]2[O:9]3)=[O:38])=[CH:35][CH:34]=1
Reactant: OC1=C(O)[C@H](O)[C@@H]2OC[C@H]1O2
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O[C@@H]2C=C[C@H]3CO[C@@H]2O3)cc1
Yield: 78.5 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.04 g (20.0 mmol) of 4-methoxybenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 41 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1) to obtain 2.06 g (yield: 78.5%) of 1,6-anhydro-3,4-dideoxy-2-O-(4-methoxybenzoyl)-β-D-eryt hro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane and diethyl ether.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:42]>>[Cl:42][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CN1C(=O)OC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Di-tert-butyl 5-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (16.7 mmol, 7.0 g), N,N′-diisopropylethylamine (51.9 mmol, 9.0 ml) and POCl3 (80 mL) were mixed and stirred at room temperature for 18 hours. The solution is concentrated in vacuo and cooled to 0° C. in an ice bath. The reaction is then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics are dried with Na2SO4 and the solvent removed in vacuo. LC-MS: 437 [M+H]. The resulting oil was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH3:29])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COc1ccccc1CNCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (63.9 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (1.3 ml) and then added with 2-methoxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0350 ml) and trimethyl orthoformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0560 ml), followed by stirring at room temperature for 30 minutes. The solution was added with sodium borohydride (19.3 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. Then, the residue was added with water and extracted with chloroform, and the extract was washed with saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and treated with hydrochloric acid. The residue was purified through a solid-phase extraction column (Sep-Pack®, tC18, manufactured by Waters Corporation), thereby obtaining hydrochloride (6.80 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8].Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)/[C:20](=[N:26]/[OH:27])/[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8]
Reactant: NO
Reactant: CO[C@]1(c2csc(Sc3ccc4c(c3)CCC4=O)c2)CCO[C@@H]1C
Agent: Cl
Product: CO[C@]1(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCO[C@@H]1C
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one oxime in 87% yield, m.p. 140°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]>C(OC(=O)C)(=O)C>[C:4]([O:15][CH2:14][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:12]=[CH:11][N:10]=1)(=[O:3])[CH3:5]
Reactant: CCOC(=O)CCc1cc[n+]([O-])c(C)c1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCc1ccnc(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(3-ethoxy-3-oxopropyl)-2-methylpyridine 1-oxide (1.99 g) and acetic anhydride (10 mL) was stirred at 100° C. for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C:14](=[O:15])[C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([Mg]Br)#[CH:36]>C1COCC1>[C:1]([O:9][C@@H:10]1[C@:14]([C:35]#[CH:36])([OH:15])[C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: O=C(OC[C@H]1O[C@H](OC(=O)c2ccccc2)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
Alternatively, the same procedure as that described in step 2 can be used, except that the reaction temperature is −30° C. and the reaction time is 3 hours, using (2R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-dihydrofuran-3-one (1.0 g, 2.17 mmol, 1.0 equiv.), 1M ethynylmagnesium bromide (13 ml, 6.51 mmol, 3 equiv.) CeCl3 (1.77 g, 7.16 mmol, 3.3 equiv.) and THF (18 ml), to give (2R,3R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydrofuran-3-ol.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of ethyl 3-oxo-3-(4-pyridyl)propionate (13.9 g, 72.0 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 2.88 g, 72.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (17.2 g, 72.0 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml), and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10.9 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.[N:20]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:28][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH:13]=1
Reactant: NC(=O)N1CCOCC1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Product: COC(=O)c1ccccc1NCc1ccnc(NC(=O)N2CCOCC2)c1

Procedure:
2-({2-[(Morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and morpholine-4-carboxylic acid amide in analogy to the procedures detailed in WO2004/013102, particularly Example 6A, supra; 1H-NMR (300 MHz, d6-DMSO) 9.19 (1H, s), 8.15-8.19 (2H, m), 7.79-7.84 (2H, m), 7.29-7.34 (1H, m), 6.92 (1H, dd), 6.56-6.62 (2H, m), 4.50 (2H, d), 3.83 (3H, s), 3.57-3.60 (4H, m), 3.42-3.46 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]1[CH:31]=[C:30]([CH:32]=O)[C:29]([CH3:34])=[N:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:30]3[C:29]([CH3:34])=[N:28][N:27]([CH3:26])[CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1C=O
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1-c1nc2c(N3CCN(Cc4ccc(Cl)cc4)CC3)c(Cl)cnc2[nH]1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.076 g, 0.20 mmol) and EtOH (4.0 mL) was added 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (0.027 g, 0.22 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.85 mL, 0.85 mmol). The reaction mixture was stirred at 80° C. for 24 h, it was then allowed to cool to room temperature, concentrated in vacuo, and the residue was absorbed on silica gel and placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v/v; 1:1), and then 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1) afforded the title compound as a white solid after trituration with diethyl ether (0.023 g, 25%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]2[C:5](=[O:19])[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=3[C:9]=2[CH3:10])[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4F)CC3)c(=O)oc2c1
Yield: 42 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(2-fluorophenyl)piperazine; yield 42%; m.p. 152°-153° C. (from ethanol).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:5]=2[O:4]1)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([Cl:21])=[O:18])=[CH:15][C:5]=2[O:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1Oc2cc(C(=O)O)ccc2N(CC)C1=O
Product: CC[C@H]1Oc2cc(C(=O)Cl)ccc2N(CC)C1=O

Procedure:
A mixture of (R)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.0 g) in thionyl chloride (10 ml) was stirred under reflux for 2 hours. Thionyl chloride was distilled off under reduced pressure to give (R)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbonyl chloride (1.14 g).