Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[NH:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.CC(C)([O-])C.[K+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:5]([CH2:34][O:33][CH2:31][CH3:32])[C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: CCOCCl
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(Sc2ccc(Cl)c(Cl)c2)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCn1c(Sc2ccc(Cl)c(Cl)c2)c(Br)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of 4-bromo-2-(p-chlorophenyl)-5-[(3,4-dichlorophenyl)thio]pyrrole-3-carbonitrile (0.644 g, 1.40 mmol) and potassium tert-butoxide (0.173 g, 1.54 mmol) in tetrahydrofuran is stirred at room temperature for 30 minutes, treated with chloromethyl ethyl ether (0.16 mL, 1.54 mmol), stirred overnight at room temperature, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ethyl acetate/hexanes solution to give the title product as a white solid (0.554 g, mp 105°-107° C.).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:17]=[C:18]([CH2:23][S:24]([CH2:27][C@@H:28]([CH3:32])[C:29]([OH:31])=[O:30])(=[O:26])=[O:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1>C(O)CC.CCOC(C)=O>[CH3:32][C@H:28]([CH2:27][S:24]([CH2:23][C:18]1[CH:19]=[C:20]([CH:21]=[CH2:16])[CH:22]=[C:1]([CH3:2])[CH:17]=1)(=[O:25])=[O:26])[C:29]([OH:31])=[O:30]
Reactant: Cc1cc(Br)cc(CS(=O)(=O)C[C@@H](C)C(=O)O)c1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=Cc1cc(C)cc(CS(=O)(=O)C[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Potassium vinyltrifluoroborate (247 mg, 1.8 mmol), triethylamine (0.21 ml, 1.5 mmol) and [1,1′-bis(diphenylphosphino-κP)ferrocene]dichloro-palladium (24 mg) are added to (S)-3-(3-bromo-5-methyl-phenylmethanesulfonyl)-2-methyl-propionic acid (0.5 g, 1.5 mmol) in 25 ml propanol. The mixture is stirred under argon for 2.5 hrs at reflux. After cooling to rt the mixture is diluted with EtOAc, washed with 0.5 N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and the solvents are evaporated. The residue is purified by chromatography on silica gel (flashmaster, DCM to DCM/methanol 9/1) followed by crystallization from DCM/diethyl ether/hexane to give the title compound as off-white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:28][OH:29]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:28][OH:29])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NO
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)CC(C)C
Agent: Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(CC(C)C)=NO

Procedure:
By the general method described in Part F of Example 30, 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one was reacted with hydroxylamine hydrochloride to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one oxime in about a 5 to 1 mixture of E and Z isomers as a white solid after recrystallization from aqueous methanol, mp 207-209° C.
Reaction SMILES: CN(C=O)C.CS(C)=O.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:21][O:22][C:23](=[O:38])[C@H:24]([CH2:36][OH:37])[NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>CN(C=O)C>[CH2:29]([O:28][C:26]([NH:25]/[C:24](=[CH:36]\[O:37][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11])/[C:23]([O:22][CH3:21])=[O:38])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/OS(=O)(=O)c1ccc(C)cc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a pre-cooled (−30° C.) solution of DMF:DMSO (1:1, 200 mL) under nitrogen was added TsCl (76.3 g, 0.4 mol) in small portions over 30 min. NOTE: This reaction is highly exotermic and careful temperature control is essential! The solution was stirred at −10° C. for 10 min, then again taken to −30° C. A solution of cbz-L-serine methyl ester (20.3 g, 0.08 mol, CAS 1676-81-9) in DMF was added dropwise, again with careful temperature control. After stirring for 10 min at −30° C. triethylamine (110 mL, 0.79 mol) was added and the reaction was slowly taken to 0° C. and kept at this temperature for 2 h. The reaction was quenched by addition of ice-cold water. The solution was extracted with 3×EtOAc, then the combined organic layer was washed extensively with brine and water. Drying and evaporation gave product as yellow oil (30 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[C:42]([CH3:43])[C:35]=12.C(#N)C>C(Cl)Cl>[Cl:33][C:34]1[C:35]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Cc1cnc2[nH]cnc(Cl)c1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.06 g, 2.1 mmol) in CH2Cl2 (30 mL) was added HBr (5.7 M in acetic acid; 2.2 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×15 mL). The resulting oil was dissolved in MeCN (10 mL) and added dropwise into a solution of the sodium salt of 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Med. Chem. 33: 1984 (1990)] (0.62 g, 3.7 mmol) in anhydrous acetonitrile (70 mL), and NaH (60% in mineral oil, 148 mg, 3.7 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (250+100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×5 cm) using hexane/ethyl acetate (9/1, 5/1, 3/1) gradient as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.87 g) as a colorless foam.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:29])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([O:21][CH:16]1[CH:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:29])[CH2:19][C:18](=[O:20])[O:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(NC(=O)C2CCCN2)C(OCc2ccccc2)O1

Procedure:
A solution of 118 (405 mg, 1.0 mmol) was treated with TFA (2 mL) in CH2Cl2 (2 mL) for one hour. The reaction solution was evaporated in vacuo and azeotrapped with CH2Cl2 four times to give pyrrolidine-2-carboxylic acid (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-amide as a pale yellow solid. 1H-NMR (500 MHz, CDCl3): δ 1.87-2.15 (m, 4H), 2.30-2.70 (m, 2H), 2.80-3.08 (m, H), 3.45 (br, 2H), 4.35-4.98 (m, 3H), 5.30-5.56 (m, H), 7.10-7.60 (m, 5H); Analytical HPLC: 7.78/8.20 min.; LC-MS: m/e=305 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:15][N:14]=[C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: ON=C1CCCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.6 %

Procedure:
Potassium t-butoxide (19 g, 1600 mmol) was added in portions to a cooled (2° C.) solution of cycloheptanone oxime (19 g, 150 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 40 minutes and then 1-chloro-4-nitrobenzene (25 g, 160 mmol) in DMF (50 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 2 hours, and then stood at ambient temperature for 16 hours. The reaction mixture poured into water (1600 mL) with stirring. The mixture was stirred for an additional 20 minutes and then allowed to stand at room temperature for 5 hours. The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from hexane provided cycloheptanone O-(4-nitro-phenyl)-oxime (30 g). Cycloheptanone O-(4-nitro-phenyl)-oxime (12 g, 50 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (17 mL) was added. The reaction mixture was heated to reflux for 4 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (7.8 g, 34 mmol). A mixture of 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (5.8 g, 25 mmol) and Raney nickel (-5.6 g wet weight) in ethanol (270 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (gradient elution with 15-25% ethyl acetate-hexanes) to give 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (4.6 g). Mp 98-99° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[C:16](Cl)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C(N(C(C)C)C(C)C)C.[NH:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[C:16]([N:34]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]3)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3)c2n1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
3-benzyl-5-tert-butyl-7-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (192.2 g, 548 mmol, Eq: 1.00) was charged in the reactor followed by Acetonitrile (780 g, 1.0 l) and N-Ethyldiisopropylamine (108 g, 143 ml, 822 mmol, Eq: 1.5). (S)-Pyrrolidin-3-ol (54.1 g, 51.6 ml, 603 mmol, Eq: 1.1) was added dropwise over 30 min at Tr=20 to <30° C. After 2 h at 25° C., the reaction mixture was transferred with Toluene (865 g, 1.0 l) into a 3 l round bottom flask and it was concentrated on a rotary evaporator, to switch solvent to toluene. The toluene solution was washed with a 10% aqueous citric acid solution (1.0 l). The aqueous phase was separated and extracted with toluene (434 g, 500 ml). The org. phases were washed sequentially with half saturated aqueous NaHCO3 (500 ml) and half saturated aqueous NaCl (500 ml). The org. phases were combined, dried over MgSO4 and concentrated at 45° C. to ca 500 mL. Heptane (684 g, 1.0 l) was added under stirring. After 5-10 min the product started to crystallize. The white suspension was stirred for 2 h at RT and was filtered. The white filter cake was washed with heptane (274 g, 400 ml) and dried at 45° C./5 mbar to give 186.9 g of the title compound as a white powder. MS (m/e): 353.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])[CH:3]=1.Cl.N1C=CC=CC=1.[CH3:27][NH:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)=[O:30].C(OCC)(=O)C>C(OC(O)C)C.CO>[CH3:27][NH:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH:40][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])[CH:3]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)=[O:30]
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Cl)ccn1
Reactant: CNC(=O)n1ccc2cc(N)ccc21
Agent: CCOC(C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CCN(CC)CCCNC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)NC)c2)ccn1
Temperature: 130 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
1-(4-Chloropyridin-2-yl)-3-(3-diethylaminopropyl)urea (30 mg, 0.11 mmol) was dissolved in ethoxyethanol (1.1 ml); pyridine hydrochloride (24 mg, 0.22 mmol) and 5-aminoindole-1-carboxylic acid methylamide (22 mg, 0.12 mmol, Production example 218-2) was added thereto; and the reaction mixture was stirred at 130° C. for 2 hours. After cooled down to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:3, ethyl acetate, ethyl acetate:methanol=93:7 in this order) to yield the title compound (8 mg, 0.018 mmol, 17%) as pale yellow powder.
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.IC.Cl>C1COCC1.C(O)C>[Cl:16][C:17]1[C:22]([CH3:1])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Solvent: CCO
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ncc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-butyllithium (3.8 mL, 2.5M in hexane, 9.4 mmol) in THF (40 mL) cooled to −30° C. under nitrogen was added 2,2,6,6-tetramethylpiperidine (1.7 mL, 10.1 mmol). This solution was allowed to warm to 0° C. over 20 min. and was then cooled to −70° C. A solution of 2,6-dichloropyrazine (1 g, 6.7 mmol) in THF (40 mL) was added dropwise and the resulting brown solution stirred at −70° C. for 30 min. Iodomethane (4.1 mL, 67 mmol) was then added and the solution stirred at −70° C. for a further 45 min after which time a mixture of ethanol (5 mL), THF (5 mL) and 1N HCl (1 mL) was added. The solution was allowed to warm to room temperature and was concentrated under reduced pressure. The residue was dissolved in H2O (50 mL) and the product extracted into dichloromethane (3×30 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL) and dried (Na2SO4). The organic layer was concentrated in vacuo and the residue purified by column chromatography eluting with dichloromethane-hexane (1:1) to separate the product as a clear motile oil (820 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][N:13]1[C:18]([NH:19][CH2:20][CH2:21]CNC2C=CC([N+]([O-])=O)=CC=2)=[CH:17][C:16](=[O:33])[N:15]([CH3:34])[C:14]1=[O:35].[CH2:36]([N:38](CC)CC)[CH3:37]>C(O)(C)C>[CH3:12][N:13]1[C:18]([N:19]2[CH2:20][CH2:21][N:38]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:36][CH2:37]2)=[CH:17][C:16](=[O:33])[N:15]([CH3:34])[C:14]1=[O:35]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCN(CC)CC
Reactant: Cn1c(NCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Solvent: CC(C)O
Product: Cn1c(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
First, 0.48 g of 4-nitrobenzyl bromide, 0.5 g of 1,3-dimethyl-6-(piperazin -1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 0.5 ml of triethylamine were suspended in 5 ml of isopropanol, and the resulting suspension was then heated under reflux for 8 hours. Afterward, the used solvent was removed from the resulting reaction mixture by distillation under reduced pressure, and the residue was dissolved in chloroform and was then washed with water. The washed organic layer was dried over anhydrous sodium sulfate. Furthermore, the dried organic layer was subjected to distillation under reduced pressure so as to remove the solvent therefrom, and the residue was then purified through a silica gel column chromatograph (chloroform/methanol=50/1 to 20/1 in terms of volume ratio) in order to obtain 0.88 g of 1,3-dimethyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH2:21][CH2:20][N:19]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Oc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(O)cccc21
Yield: 57.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of 2,3-dihydro-1H-indol-4-ol, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 205 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:15][C:13]=2[N:14]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) as a TFA salt (708 mg, 2.0 mmol) in anhydrous DMF (5 ml) was added triethylamine (5550, 4.0 mmol) and the reaction was stirred at RT for two hours. After this time, ethyl chloroformate (228 μl, 2.4 mmol) was added dropwise and the reaction was stirred at RT overnight. The reaction was partitioned between water and ethyl acetate and the aqueous phase was extracted into ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulphate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:3]=[C:4]([CH3:20])[C:5]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(I)cc(C)c1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: COC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc(C)c1OCCN1CCCC1

Procedure:
Prepared according to general working method I from methyl 5-iodo-3-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-benzoate (150 mg, 0.39 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (112 mg, 0.53 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6][C:7]1=[O:12]
Reactant: COC(=O)c1ccn(C)c(=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
The title compound of example 24 (4.0 g, 23.9 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (5.8 mL, 119 mmol) was added and the reaction was stirred at 78° C. for 3 hours. The reaction mixture was then cooled to room temperature and the product was filtered off to give 3.13 g (78% yield) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=3)[N:16]=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36]>CN(C)C=O.CCOC(C)=O.[Cu]I.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:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:21]=3)[N:16]=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(C#CCN4CCOCC4)cc3c2=O)cc1
Temperature: 50 °C

Procedure:
To a solution of 300 mg (0.648 mmol) of 4-(6-iodo-4-oxo-4H-quinazolin-3-ylmethyl)-benzoic acid tert-butyl ester (preparation described above) in 50 mL of dimethylformamide (“DMF”), was added diisopropylamine (4 mol eq.), a catalytic amount of CuI, 4-prop-2-ynyl-morpholine (4 mol eq.), and Pd(PPh3)2Cl2 (a catalytic amount). The reaction mixture was then heated to 50° C. for 15 hours. The reaction was then diluted with 200 mL of EtOAc, and washed with 2×200 mL water, and 1×200 mL brine. The organic layer was dried over MgSO4 and concentrated. The residue was then passed through a silica gel column, elution with 4:1 EtOAc:tetrahydrofuran (“THF”). The product is carried directly to the next step.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].CC(C1C=C(S[C@@H]2CC[CH2:40][C@H:39]2[OH:43])C=C(C(C)(C)C)C=1)(C)C.CC(C1C=C(C(C)(C)C)C=CC=1S[C@H]1CCC[C@H]1[OH:64])(C)C>C(Cl)(Cl)Cl>[CH3:14][C:11]([C:9]1[CH:8]=[C:7]([S:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[O:22][CH2:40][C:39]([OH:43])=[O:64])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method described in Example 77, except that the title product of Example 87 was substituted for the title product of Example 75, Compound A. The structure was supported by NMR, Ir optical rotation (CHCl3, 25° C.; 589 nm -42.5°±2.69°; 365 nm 138.4°±18.1°) and elemental analysis.