Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:68]1([CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:71]3[CH2:72][CH2:73][N:68]([CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:69][CH2:70]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)ccn3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol), HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl piperazinoacetate (168 mg, 0.98 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give to the crude, which was purified by silica gel chromatography eluting with 5-8% of methanol in chloroform to afford ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetate as white solid. Yield: 250 mg, 63%.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.Cl.Cl.[CH3:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[N:6]=[C:5]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][C:15]3[CH:24]=[CH:25][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)[CH2:23][CH2:22]2)[S:4][N:3]=1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Reactant: Clc1nc(Br)ns1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(Br)ns3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (300 mg, 1.5 mmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (485 mg, 1.65 mmol) and DIPEA (641 mg, 867 μl, 4.96 mmol) in EtOH (10 mL) was stirred over night at ambient temperature. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 489 mg (85%) of the title compound as off-white solid. MS (m/e): 383.2 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([CH3:21])=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].[Cl-].C[N+]1C=CC=CC=1Cl.[Cl-].[NH2:32][C:33]([NH2:35])=[NH2+:34].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[NH2:34][C:33]([NH2:35])=[N:32][C:8](=[O:9])[C:7]1[C:11]([CH3:21])=[CH:12][C:13]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: NC(N)=[NH2+]
Reactant: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 0.25 h

Procedure:
1.0 g of 3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzoic acid [obtainable by reacting 3-methylsulfonyl-4-chloro-6-methylbenzoic acid with 3-hydroxypyridine] is dissolved in 15 ml of 1-methylpyrrolidone, and 0.67 g of 1-methyl-2-chloropyridinium chloride is added to this solution, which is stirred for 15 min. 0.9 g of guanidinium chloride and 2.6 ml of N-ethyldiisopropylamine are then added, and the mixture is stirred at room temperature for one hour. Following customary working-up, N-diaminomethylene-3-methylsulfonyl-4-(3-pyridyloxy)-6-methylbenzamide is obtained, m.p. 221-224°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH2:40]C)[C:31]=3[CH:42]=2)=[CH:5][CH:4]=1.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>>[N:43]1([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:42]=3)=[CH:7][CH:8]=2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: c1c[nH]cn1
Reactant: CCOCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21

Procedure:
Analogously to Example 269a, 0.103 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-ethoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.013 g of imidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.47 (200:10:1 dichloromethane-methanol-25% conc. ammonia). Rt=4.34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]2[CH:21]=1.[CH3:22][N:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][N:23]([CH3:24])[C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][C@@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]3[CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)C[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](CO)Nc1c(C(N)=O)cnn2cc(-c3cccc(N(C)C)c3)cc12
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 13.7 %

Procedure:
A mixture of (S)-6-bromo-4-(1-hydroxy-4-methylpentan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (23 mg, 0.070 mmol), 3-(N,N-dimethylamino)phenyl boronic acid (16 mg, 0.1 mmol), palladium (II) acetate (1.46 mg, 0.0065 mmol), potassium phosphate, tribasic, 2M (0.1 mL, 0.2 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (6.2 mg, 0.013 mmol) in dioxane (Volume: 0.65 mL) was heated to 90° C. overnight. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.8 mg, 15% yield). MS (ES+) m/z: 396.1 (M+H); LC retention time: 1.83 min (analytical HPLC Method B).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:11][C:10]=1[O:9][CH2:8][CH:7]([OH:26])[CH2:6][NH:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NCC(O)COc1cc(C2=NNC(=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)NCC(O)COc1cc(C2=NNC(=O)CC2)ccc1N

Procedure:
A solution of 6-[3-(3-t-butylamino-2-hydroxypropoxy)-4-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone in ethanol was heated under reflux with palladium on charcoal and excess of cyclohexene for 18 hours. Evaporation of the filtered solution under reduced pressure gave 6-[4-amino-3-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:22][O:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccccc2C[C@H]1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@@H]1Cc2ccccc2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of 2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (0.860 g, 0.00308 mol) in THF (30 mL) at 0° C. under an atmosphere of nitrogen was added a 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 20 minutes, followed by the addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir and warm to rt over 18 h. The reaction was monitored by 1H NMR. The reaction mixture was then re-cooled to 0° C. To the reaction mixture was added 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 15 minutes, followed by addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir at rt for 22 h. 1H NMR indicated 80:20 product/starting material. The reaction was quenched with aqueous 1N HCl solution and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The oil was purified by silica gel chromatography, eluting with a gradient of hexanes to 10% EtOAc in hexanes) to obtain product (4.18 g, 46%). LC/MS: Rt=1.90 min, ES+ 294 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(OCC)(=O)C.O>[Cl:15][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Oc1ncc2ccc(Cl)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2cnc(Cl)nc2c1
Temperature: 110 °C

Procedure:
In a 250 mL three neck round bottom flask, 7-chloroquinazolin-2-ol (19 g, 105.55 mmol) was suspended in freshly distilled POCl3 (190 mL) at rt. The resulting suspension was heated to 110° C. for 4 h. On completion of reaction, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (200 mL) and cold water (200 mL). The organic layer was separated and the aqueous phase was re-extracted with ethyl acetate (500 mL×2). The combined EtOAc extract was washed with brine and concentrated under reduced pressure. The residue (pale brown) obtained was purified by silica gel (60-120 mesh) column chromatography and gradient elution with 12-20% ethyl acetate-hexanes gave 2,7-dichloroquinazoline as a pale yellow solid. Yield: 7 g (33.5%). LCMS (ESI, m/z): 199 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH2:15])[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
To a solution of [tert-butoxycarbonyl-(5-chloro-2-nitro-benzyl)-amino]-acetic acid ethyl ester (69.0 g, 0.186 mol) in ethyl acetate (1200 ml) was added zinc bromide (8.5 g, 0.037 mol). The reaction mixture was purged with argon after 15 min. After addition of the palladium catalyst (10% on activated charcoal, 7.9 g, 0.0074 mol) the mixture was hydrogenated at ambient pressure during a period of ca. 48 h until ca. 13 l of hydrogen gas had been consumed. The catalyst was removed by filtration and the filtrate was washed with two portions of saturated aqueous sodium bicarbonate solution and brine, each. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (60.6 g, 95.5%) as yellow waxy solid. MS m/e: 343 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH:30]=[C:29]([C:9]3[CH:8]=[N:7][C:6]4[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4cccc(Br)c4n3)cn2)CC1
Temperature: 80 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-chloro-quinoxaline (Step 1.4, 1 g, 4.11 mmol), 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.74 g, 3.70 mmol), K3PO4 (2.67 g, 12.3 mmol) and of PdCl2(PPh3)2 (88.2 mg, 0.123 mmol). After several cycles of vacuum/purge with argon, a mixture of 5 ml of DMA and 220 μl deionized water is added. The reaction mixture is then heated to 80° C. for 3 h. After cooling, the suspension is poured onto de-ionized water and diluted with EtOAc. The phases are separated and the aqueous phase re-extracted twice with EtOAc. The combined organic phases are washed with saturated brine and dried over Na2SO4. After filtration, the mixture is concentrated in vacuo. The residue is purified by chromatography on a 80 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient hexanes:EtOAc from 1:0=>0:1) to afford the title compound as a yellow foam, Rt=1.350 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 458 (M+1, 79Br)+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[OH:20][C:21]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[OH:20][C:21]1[CH:30]=[C:29]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1O
Yield: 36.4 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol [prepared in Example 37(d)] with 1.5 g (5.5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 739 mg (36%) of the expected compound, with a melting point of 112°-113° C., were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CN(C)C=O.[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1>C(N(CC)CC)C>[NH2:17][C:18]1[C:33]([Cl:34])=[CH:32][C:21]([C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:27][C@H:26]2[OH:31])=[O:23])=[C:20]([O:35][CH3:36])[CH:19]=1
Reactant: O=C(CCCCl)N1CCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCNC[C@H]1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3.00 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine in 67.5 parts of N,N-dimethylformamide were added 1.93 parts of trans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamide and 1.5 parts of N,N-diethylethanamine and the whole was stirred for 18 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.1 parts (47.8%) of trans-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamide; mp. 174.7° C. (compound 15).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CO)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
(3-Fluoro-benzyl)-3-(4-hydroxymethyl-thiazol-2-yl)-urea (909.52 mg) was added in a solution of Dess-Martin periodinane (0.3 M, 10.8 mL) in DCM (100 mL) at 0° C. The reaction mixture was stirred at room temperature over a couple of hours until all starting materials were consumed. After concentration, the residue was recrystallized from DCM/Hexane to afford the desired product (580 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[C:14]([O:21][CH3:22])[CH:13]=2)=[CH:6][N:5]=1.Cl.N([O-])=O.[Na+].[N-:28]=[N+:29]=[N-].[Na+].C(=O)(O)[O-].[Na+]>O>[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:13]=[C:14]([O:21][CH3:22])[C:15]([N:20]=[N+:28]=[N-:29])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:6][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N=[N+]=[N-]

Procedure:
A solution of 7 g. of 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)pyrimidine dihydrochloride in 60 ml. of 1N hydrochloric acid and 40 ml. of water was treated over a period of 5 minutes with stirring and ice-cooling with a solution of 1.52 g. of sodium nitrite in 10 ml. of water. After stirring at 0° C. for 30 minutes, a solution of 1.43 g. of sodium azide in 20 ml. of water was added. The solution was stirred at 0° C. for 2 hours and then treated with sodium bicarbonate to obtain an alkaline reaction. After stirring at 0° C. for 1 hour, the precipitate was removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-(4-azido-3,5-dimethoxy-benzyl)pyrimidine having a melting point of 152° C. (decomposition).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:18])[N:4]2[CH2:3][CH2:2][O:1][C:6]3[C:5]2=[C:10]([CH:9]=[CH:8][CH:7]=3)[C:22]=1[OH:23])=[O:15])[CH3:12]
Reactant: c1ccc2c(c1)NCCO2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dihydro-2H-1,4-benzoxazine (6 g) and tri(ethoxycarbonyl)methane (9.4 ml) was stirred at 150° C. for 1 hour and at 200° C. for 1 hour. The mixture was cooled and the solid was washed with ether to give pale brown crystals of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (9.6 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=O)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.C[Si](C)(C)[C:27]#[N:28].C(=O)(O)[O-].[Na+]>O1CCCC1.[H-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2]>[C:27]([CH:13]1[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][NH:14]1)#[N:28]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [Zr+2]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-yl]carbamate (0.67 g, 1.97 mmol) in tetrahydrofuran (10 mL) was slowly added to a solution of zirconocene chloride hydride (0.76 g, 2.95 mmol) in tetrahydrofuran (5.0 mL) at −20° C. After 15 min, the mixture was allowed to warm to ambient temperature. After 3 h, trimethylsilanecarbonitrile (1.31 mL, 9.84 mmol) was added. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with Rochelle's salt (1.0 M in water), brine, dried over sodium sulfate, filtered, and concentrated. MS 352.1 (M+1).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]1[C:12]([CH3:17])=[N:13][CH:14]=[C:15]([CH3:16])[C:9]1=[C:8]2[CH2:18][CH2:19][N:20]([CH3:24])[CH:21]([CH3:23])C)C.[CH2:25](C1C2=C(CCN(C)C(C)C)C3C(N2C(C)=NC=1C1C=CC=CC=1)=CC=CC=3)CCC>>[CH2:24]([N:20]([CH2:21][CH3:23])[CH2:19][CH2:18][C:8]1[C:7]2[C:11](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:10]2[C:12]([CH3:17])=[N:13][CH:14]=[C:15]([CH3:16])[C:9]=12)[CH3:25]
Reactant: CCc1cccc2c(CCN(C)C(C)C)c3c(C)cnc(C)n3c12
Reactant: CCCCc1c(-c2ccccc2)nc(C)n2c1c(CCN(C)C(C)C)c1ccccc12
Product: CCN(CC)CCc1c2ccccc2n2c(C)ncc(C)c12

Procedure:
Similarly, by replacing 5-(2-chloroethyl)-1,4-dimethylpyrimido-[1,6-a]indole with an equivalent amount of another compound of formula 1 described in Example 12 and using N-methyl-N-(1-methylethyl)amine, the following compounds of formula 1 are obtained, respectively; 9-ethyl-1,4,N-trimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine, 8-methoxy-1,4,N-trimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine,7-phenylmethoxy-1,4,N-trimethyl-N-(1-methylethyl)pyrimido-[1,6-a]indole-5-ethanamine,1,N-dimethyl-N-(1-methylethyl)-4-propylpyrimido[1,6-a]indole-5-ethanamine,3,4-diethyl-1,N-dimethyl-N-(1-methylethyl)pyrimido[1,6-a]indole-5-ethanamine,1,4-diethyl-N-methyl-N-(1-methylethyl)-3-phenylpyrimido[1,6-a]indole-5-ethanamine, and 4-butyl-1,N-dimethyl-N-(1-methylethyl)-3-phenylpyrimido[1,6-a]indole-5-ethanamine.