Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]1([C:26]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][C:33]3[NH:32][N:31]=[C:30]([C:35]([NH2:37])=O)[C:29]=3[CH:28]=[CH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:38]1([C:26]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:34][C:33]3[NH:32][N:31]=[C:30]([C:35]#[N:37])[C:29]=3[CH:28]=[CH:27]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NC(=O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
0.845 cm3 of pyridine and 0.74 cm3 of trifluoroacetic anhydride are successively added dropwise to a solution, cooled to a temperature in the region of 5° C., of 1.1 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide in 100 cm3 of dioxane. After warming to a temperature in the region of 20° C., the reaction mixture is stirred for about 20 hours at this temperature. 2 cm3 of pyridine and 2 cm3 of trifluoroacetic anhydride are added to the solution and the reaction mixture is refluxed for about 4 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of water and 150 cm3 of ethyl acetate; the pH of the mixture is brought to the region of 8 by addition of sodium bicarbonate. After separation of the phases by settling, the aqueous phase is extracted with three times 50 cm3 of ethyl acetate, and the combined organic phases are washed with three times 50 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)]. 0.8 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carbonitrile is thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[CH2:21][C@@:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]3=[O:20])[CH2:10][C:7]2=[N:8][CH:9]=1.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[I:3][C:4]1[CH:5]=[C:6]2[CH2:21][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[C:12]3=[O:20])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)cnc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(I)cnc3C2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.242 g, 6.06 mmol) was added portionwise to a solution of (6S)-3-iodo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 4) (2.00 g, 5.51 mmol) in DMF (50 mL) at 0° C. After stirring for 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.06 mmol) was added dropwise. The resulting mixture was warmed slowly to ambient temperature and stirred for 48 h. The reaction was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—95:5 to 50:50, to give the title compound. MS: m/z=493.9 (M+1).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)CC>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Clc1nccn2c(C3CCCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N
Solvent: CCC(C)O
Solvent: O
Product: Nc1nccn2c(C3CCCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
20 M NH3 in H2O (4 mL) was added to a suspension of 8-chloro-3-cyclohexyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (82 mg, 0.20 mmol) in 2-butanol (0.9 mL). The mixture was heated in an oil bath set at 105° C. overnight. The reaction was stopped at this time and concentrated in vacuo. Purification by prep TLC using 3% NH3 in MeOH in DCM afforded 41.4 mg of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3): δ=1.27-1.52 (m, 3H), 1.73-1.96 (m, 5H), 1.99-2.10 (m, 2H), 2.84-3.02 (m, 1H), 5.28 (br. s., 2H), 7.01-7.08 (m, 3H), 7.09-7.14 (m, 3H), 7.23 (d, J=5.31 Hz, 1H), 7.32-7.40 (m, 2H), 7.58-7.65 (m, 2H). MS (ES+): m/z 385.03 (100)[MH+]. HPLC: tR=2.83 min (Open Lynx polar—5 min).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:27][C:28]([C:30]2[N:34]3[CH:35]=[CH:36][C:37]([CH2:39][CH:40]=O)=[CH:38][C:33]3=[N:32][CH:31]=2)=[O:29])[N:20]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[N:19]=1)[CH3:17]>C(Cl)Cl.C(O)(=O)C>[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:27][C:28]([C:30]2[N:34]3[CH:35]=[CH:36][C:37]([CH2:39][CH2:40][N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)=[CH:38][C:33]3=[N:32][CH:31]=2)=[O:29])[N:20]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[N:44]=2)[N:19]=1)[CH3:17]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Reactant: FC1CNC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC(F)C5)ccn34)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-fluoroazetidine hydrochloride (61 mg, 0.55 mmol) in DCM (2 mL) was treated at ambient temperature with Hunig's base (0.10 mL, 0.57 mmol). To the hazy solution was added N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (prepared according to (Example 127, Steps A-B; 50 mg, 0.11 mmol) (prepared according to the procedure for Example 127) and the (10 equivalents) was added, followed by 2 drops of glacial acetic acid, and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to preparative thin-layer chromatography on silica, with a 10% MeOH-DCM mixture as eluent to afford the desired product (10 mg) as a white solid. MS (ES+APCI) m/z=512 (M+H) detected.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>[Pd].COCCOCCOC>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1c(nc(N)[nH]c1=O)CC2
Agent: [Pd]
Solvent: COCCOCCOC
Product: Cc1cc(C)c2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
A mixture of 3-amino-5,6-dihydro-7,9-dimethylbenzo[f]quinazolin-1(2H)one (0.25 g, 1.04 mmole) and 10% palladium on carbon (0.5 g) in diglyme (25 ml) was vigorously stirred and refluxed under a nitrogen atmosphere for 2.5 hours, and then filtered while still hot through a bed of celite. Diglyme was removed from the filtrate under reduced pressure, and the residue was triturated with hot methanol, filtered, washed with methanol and ether, and dried to give 3-amino-7,9-di- methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.14 g, 55%) 1H NMR(DMSO-d6 6 200MHz) δ: 2.43(s, 3H, CH3); 2.60(s, 3H, CH3); 6.48(s, 2H, NH2); 7.14(s, 1H, Ar); 7.25(d, J=9.2 Hz, 1H, Ar); 8.11(d, J=9.1 Hz, 1H, Ar); 9.38(s, 1H, Ar); 11.07(s, 1H, NH).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].C(O[N:16]=[O:17])(C)(C)C.[ClH:18].[NH2:19][CH2:20][C:21]#[N:22].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl.O1CCCC1>[ClH:18].[ClH:18].[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2=[N:19][CH:20]=[C:21]([NH2:22])[N+:16]([O-:17])=[C:6]2[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)(C)ON=O
Reactant: CCN1CCCC(=O)CC1
Reactant: N#CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCN1CCc2ncc(N)[n+]([O-])c2CC1
Reaction time: 8 h

Procedure:
First 23 gm (0.16 mol) of 1-ethyl-hexahydro-azepin-4-one and then 19.2 ml of tert.butylnitrite were added dropwise to a mixture of 19 gm (0.16 mol) of potassium tert.butylate and 200 ml of absolute tetrahydrofuran at -40° C., and the resulting mixture was allowed to stand overnight at 0° to 10° C. Thereafter, a solution of 20 gm (0.217 mol) of amino-acetonitrile hydrochloride and 30 gm of N-ethyl-diisopropylamine in 280 ml of chloroform was added, and the resulting mixture was refluxed for 4 hours, then filtered, and the filtrate was evaporated. The desired compound was isolated from the isomer mixture residue by silicagel chromatography with acetone/concentrated ammonia (95:5). The dihydrochloride was precipitated from ethanol with ethanolic hydrochloric acid.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CCO)OCCCCO
Yield: 79.9 %

Procedure:
414 g (3.0 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 9) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 504 g (80% of theory) of 4-hydroxybutyl ethyl(2-hydroxyethyl)phosphinate as colorless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2].[Br:34][C:35](Br)=[N:36][OH:37].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:37][N:36]=[C:35]([Br:34])[CH:15]=2)[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2]
Reactant: ON=C(Br)Br
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Yield: 75.6 %

Procedure:
(2R,3 R,4R,5R)4-(acetyloxy)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate (20 mg) was stirred at 22° C. with dibromoformaldoxime (12.5 mg), sodium bicarbonate (39 mg), water (0.075 ml) and ethyl acetate (1.5 ml) for 88 h. The mixture was partitioned between water (20 ml) and ethyl acetate (3×10 ml), the organic layers were washed with brine and evaporated in vacuo to give a brown gum (19 mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 20:80-80:20) gave the title compound as a colourless gum (16.8 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.[Cl:27][CH:28]([Cl:47])[C:29]([N:31]1[C@H:35]([CH2:36][F:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=2)[O:33]C1(C)C)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1(C)C=CC=CC=1.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>[NH2:18][C:15]1([C:11]2[CH:10]=[C:9]([C:41]3[CH:42]=[CH:43][C:38]([C@@H:34]([OH:33])[C@H:35]([NH:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:47])[CH2:36][F:37])=[CH:39][CH:40]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
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: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: NC1(c2cccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc3)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
A mixture of tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (241 mg, 0.672 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (250 mg, 0.56 mmol), Cs2CO3 (365 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL) is bubbled with nitrogen gas for 2 minutes. Pd(PPh3)4 (64 mg, 0.056 mmol) is added and the resulting reaction mixture heated at 80° C. for 4 hours. Reaction is diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). Combined organic solution is dried over Na2SO4 and concentrated. Crude compound dissolved in DCM (3 mL) and stirred with TFA (0.6 mL) at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated. Crude compound is basified slowly using saturated aq. NaHCO3, extracted with ethyl acetate (3×30 mL) and combined extracts dried over Na2SO4 and concentrated. Solid dissolved in DMF (2 mL) and purified using HPLC eluting from 5 to 95% water/acetonitrile to give the title compound (50 mg): 1 HNMR (400 MHz, MeOH-d4) δ: 1.33-1.39 (m, 2H), 1.40-1.47 (m, 2H), 4.33-4.42 (m, 1.5H), 4.44-4.51 (m, 0.5H) 4.56-4.63 (m, 0.5H), 4.68-4.75 (m, 0.5H), 5.03 (d, 1H, J=4 Hz), 6.31 (s, 1H), 7.44-7.48 (m, 1H), 7.50-5.55 9 m, 3H), 7.63-7.68 (m, 3H), 7.75-7.78 (m, 1H), m/z (Cl) 411 [M+1].
Reaction SMILES: [OH:1][CH:2]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4][CH:3]1[NH:15][C:16](=[O:18])[CH3:17].[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH3:21][O:1][CH:2]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4][CH:3]1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)NC1Cc2cccc3cccc(c23)C1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1c2cccc3cccc(c23)CC1NC(C)=O

Procedure:
The N-(1-hydroxy-2,3-dihydro-1H-phenalen-2-yl)acetamide obtained is stage C of Example 1 (1 mmol, 290 mg) is dissolved in 10 cm3 of anhydrous DMF. Under an inert atmosphere, NaH (1 mmol, 0.05 g of 60% in oil suspension) and then methyl iodide (0.09 cm3, 1.2 eq) are added in the reaction mixture. Stirring is maintained at ambiant temperature for 4h30 and the solvent is evaporated. The residue is taken up in CH2 Cl2 and the solution is flitrated. The filtrate is evaporated and purified by chromatography on silica gel (particle size 60-200 μm); eluent: CH2Cl2 : MeOH 99 :-1 v/v. The title product is isolated. This is and amorphous product, which is a diastereoisomer mixture.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:16]2[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:16]2[C:25]([CH3:32])=[C:26]([N:31]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C2c3c(C)c(N4C(=O)c5ccccc5C4=O)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of phthalic anhydride (566.4 mg, 3.82 mmol) in tetrahydrofuran (5 ml) was added a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (987.3 mg, 3.38 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was refluxed with heating for 11 hours. The reaction mixture was cooled down to room temperature and then concentrated under reduced pressure. Sodium acetate (314.6 mg, 3.84 mmol) and acetic anhydride (20 ml) were added into the residue and the resulting mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled down to room temperature and then an 8 N aqueous solution of sodium hydroxide was added into the mixture until it became basic. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.16 g (81% yield) of the title compound. Melting point: 222-224° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:56][CH2:55][CH2:54][N:53]([CH3:57])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN(C)CCN
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethylethylenediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.CC(C)([O-])C.[Na+]>CS(C)=O.O>[O:11]1[CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Clc1ncccc1C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-pyridine (see PREPARATION P13.1; 3.5 g, 17.9 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.8 g, 17.9 mmol) were dissolved in DMSO (20 mL) and sodium tert-butoxide (t-BuONa) (3.4 g, 35.8 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crud product was purified by silica gel column chromatography to give the title compound (2.3 g, 7.8 mmol, yield 75%). 1H NMR (DMSO-D6, 300 MHz) δ (ppm) 1.38 (s, 9H), 2.41-2.47 (m, 2H), 3.75-3.86 (m, 4H), 4.19-4.30 (m, 4H), 5.26-5.35 (m, 1H), 6.15-6.20 (m, 1H), 7.01 (dd, 1H, J=7.31 Hz, 4.97 Hz), 7.62 (d, 1H, J=7.45 Hz), 8.02 (d, 1H, J=4.82 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:22](=[O:23])[C:20](=[O:21])[C:5]2[C@@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C@@:7]3([O:13][CH3:14])[C@H:11]4[NH:12][C@H:10]4[CH2:9][N:8]3[C:4]=2[C:3]=1[OH:24].[CH3:25]NN=NC1C=CC(C)=CC=1.C(Cl)Cl.CO>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[N:8]3[C@@:7]([O:13][CH3:14])([C@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C:5]=2[C:20](=[O:21])[C:22]=1[O:23][CH3:25])[C@H:11]1[NH:12][C@H:10]1[CH2:9]3
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: CNN=Nc1ccc(C)cc1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A 100 mg (0.30 mmole) quantity of 7-hydroxy9a-methoxymitosane and 100 mg (0.67 mmole) quantity of 3-methyl-1-p-tolyltriazene was dissolved in 2 ml methylene chloride and 10 ml diethyl ether. The solution, after gently refluxing for 6 hours was stirred at room temperature for 18 hours. TLC [methylene chloride:methanol (90:10)] revealed the appearance of a deep purple spot at Rf =0.36 with a trace amount of impurity at Rf =0.41. The reaction mixture was concentrated to dryness and chromatographed on Woelm neutral alumina employing methylene chloride and methylene chloride:methanol (30:1) as eluting solvents. Fractions containing the component at Rf =0.36 were pooled and concentrated to dryness. Precipitation of the dry residue from methylene chloride and hexane afforded the title compound as a fine amorphous purple powder (25 mg, 24%), mp 161°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].CN(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[C:1]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (62 ml) was added dropwise to a mixture of ethyl 4-amino-3-nitrobenzoate (142 g), N,N-dimethylaniline (110 ml), and toluene (940 ml) in an ice bath. After stirring the mixture at 50° C. for 3 hours, it was cooled. Water (142 ml) was added thereto to stop the reaction. The toluene layer was separated and the organic layer was washed with dilute hydrochloric acid and successively with water. After the organic layer was concentrated to about 1/3 volume, hexane (284 ml) was added thereto for crystallization. Crystals were collected by filtration and washed with hexane to obtain the desired compound, ethyl 4-(acetylamino)-3-nitrobenzoate (157.7 g).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:43])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:43][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3N)c2)CC1
Product: CN1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)c2)CC1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-Imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 563.12 [M+H]+; tR=2.67 min (System 3).