Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32](I)=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH2:36](N(CC)CC)[CH3:37]>C1COCC1.CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([C:25]2[N:29]4[CH:30]=[CH:31][C:32]([CH:36]=[CH2:37])=[CH:33][C:28]4=[N:27][N:26]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(I)ccn45)nc23)CC1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1ccn2c(-c3ccc4cccc(N5CCC(CNC(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To tert-butyl(1-(2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (91 mg, 0.16 mmol) in THF/IPA (2/1 mL) was added C2H3BF3K (31 mg, 0.23 mmol), PdCl2(dppf) dichloromethane adduct (13 mg, 0.016 mmol) and triethylamine (24 mg, 0.23 mmol). The reaction was stirred for 2 hours, followed by heating at 60° C. overnight. The reaction was then cooled to ambient temperature and concentrated, and the residue was purified by flash column chromatography (20:1 Hexane/EtOAc) providing the desired product (90% yield; 0.068 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[N:29]=[CH:30][N:31]([CH3:32])[C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3c(ncn3C)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc2c1ccn1c(=O)c(-c3ccc(OCc4ccccc4)cc3)cc(C(=O)O)c21
Yield: 92.3 %

Procedure:
2.44 g (5.5 mmol) of methyl 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo[4,5-a]quinolizine-10-carboxylate in 50 ml of ethanol were treated with a solution of 1.4 g (21 mmol) of potassium hydroxide (content 86%) in 50 ml of water. After boiling under reflux for 4 hours 200 ml of water were added and the mixture was adjusted to pH 1-2 with 2N hydrochloric acid while cooling with ice. The precipitate obtained was filtered off, washed with water and dried. There were obtained 2.16 g (92%) of 8-(4-benzyloxy-phenyl)-3-methyl-7-oxo-3,7-dihydro-imidazo [4,5-a]quinolizine-10-carboxylic acid as yellow crystals with m.p. 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N+:32]([O-])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:36][N:37](C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:36]#[N:37])[CH:30]=4)=[CH:25][CH:24]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In dichloromethane (100 ml), 4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide (1.67 g) was dissolved, followed by the addition of trimethylsilycynanide (0.42 ml) and dimethylcarbamoyl chloride (0.30 ml). The resulting mixture was stirred at room temperature for 24 hours. An aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction mixture to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (1% methanol—dichloromethane), whereby the title compound (1.44 g, 84%) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CS(C)=O.C1([O-])C=CC=CC=1.[K+].O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(I)ccc4n3)ccc12
Reactant: OB(O)c1ccccc1
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(-c5ccccc5)ccc4n3)ccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 6-[4-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-6-iodo-quinazolin-2-ylamino]-1,2-dihydro-indazol-3-one (300 mg, 0.48 mmol), and phenyl boronic acid (88 mg, 0.72 mmol) in DMSO and 1.5 M potassium phenolate (2.6 mL) was added PdCl2 (dppf)2 (175 mg) and the solution was heated to 100° C. in a sealed tube. After 12 hr, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated. The title compound was isolated by preparative HPLC as a white solid (0.82 mg). HPLC tr=5.14 min (10% to 90% MeCN over 8 min, total time 12 min, 3×150 mm C18 column) FIA m/e 475.55 (M+H), 473.55 (M−H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)=[O:7].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>>[ClH:18].[C:23]([C:22]1[CH:25]=[CH:26][C:19]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH:9]=3)[NH:13][C:12]=2[OH:17])=[N:20][CH:21]=1)#[N:24]
Reactant: COCCNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: N#Cc1ccc(Cl)nc1
Product: COCCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(C#N)cn3)c2c1
Product: Cl
Yield: 28 %

Procedure:
Starting materials: N-(2-methoxyethyl)-2-oxoindoline-5-carboxamide and 6-chloronicotinonitrile. The residue was purified on a silica gel column using a gradient chloroform/methanol, (100:1 to 10:1), as the eluent. Yield: 28% of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (s, 1H), 8.56 (m, 1H), 8.49 (m, 1H), 7.98 (s, 1H), 7.85 (dd, J=10, 2 Hz, 1H), 7.70 (d, J=10 Hz, 1H), 7.59 (dd, J=9, 2 Hz, 1H) 6.96 (d, J=9 Hz, 1H), 3.45 (m, 4H), 3.27 (s, 3H); MS (ES) m/z 337 (M++1).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].[NH2:59][N:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>C1COCC1>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:59][N:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)=[O:53])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reaction time: 8 h
Yield: 71 %

Procedure:
Hydroxybenzotriazole hydrate (64.7 mg, 0.41 mmol), N-ethyldiisopropylamine (181 ul, 1.04 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.41 mmol) were added to a mixture of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.41 mmol) and 4-aminomorpholine (41.5 μL, 0.41 mmol) in THF (15 mL) at room temperature. After stirring overnight the solvent was removed by distillation and the residue was purified by chromatography (silica, dichloromethane:methanol=98:2 to 95:5) afforded the title compound (130 mg, 70%) as a white solid. MS: m/e=445.2 [M−H]−.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][Si:17]([CH:20](Cl)[CH2:21]C)([CH3:19])[CH3:18].CN([CH:27]=[O:28])C>>[Br:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[N:6]([CH2:27][O:28][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCC(Cl)[Si](C)(C)C
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(Br)c(Cl)c(C)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (76 mg, 3.16 mmol) in dry DMF (5 ml), solution of ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 267, 420 mg, 1.58 mg) was added, the resulting mixture was stirred at 0° C. for 30 minutes until gas evolution seized. Trimethylsilyl-ethylmethyl chloride (315 mg, 1.89 mmol) was added drop wise and stirred over night while allowing the reaction mixture warmed up to room temperature slowly. The reaction was quenched with cold water, diluted with ether (20 ml), washed with water and brine, the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (95% hexanes in ethyl acetate) to give the desired product as an oil (624 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[BH4-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH3:21][S:22]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[O:2][CH3:1])[CH:8]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccccc1COc1cccc(COS(C)(=O)=O)c1
Yield: 95.3 %

Procedure:
530 mg of 3-(2-methoxybenzyloxy)benzyl alcohol obtained by reducing 3-(2-methoxybenzyloxy)benzaldehyde with sodium borohydride in ethanol was dissolved in 8 ml of methylene chloride. The solution was stirred at -5° to 0° C., 0.20 ml of methanesulfonyl chloride and 0.65 ml of triethylamine were added. The mixture was stirred at this temperature for 5 minutes. The reaction mixture was diluted with methylene chloride, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 660 mg (yield 95.3%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C2C(=CC=1OC)C(=O)CC2.N1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:11](=[O:12])[C:13](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:14]2
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: COc1cc2c(cc1OC)C(=O)CC2
Agent: O=Cc1ccncc1
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2

Procedure:
Patent application EP 711756 describes the preparation of Donepezil by reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde to give 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one. Reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpyridinium bromide. Hydrogenation in the presence of platinum oxide afforded Donepezil (Scheme 4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[NH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([S:34]([CH2:37][C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[CH2:40]Br)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[CH2:37][S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[N:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3ccccc3CS(=O)(=O)c3ccccc3)nc21
Yield: 41.8 %

Procedure:
3-[(3-Hydroxypropyl)thio]-5-methyl-7-(2-methylpropyl)-1H-pyrazolo[3,4-d]-pyrimidine-4,6(5H,7H)-dione (94 mg), potassium carbonate (90 mg) and 2-(phenylsulfonylmethyl)benzyl bromide (105 mg) were combined in dimethylsulfoxide (11 ml). After 5 hours at room temperature the reaction mixture was diluted with ethyl acetate and washed thrice with water, twice with dilute hydrochloric acid, once with brine, then dried over magnesium sulfate and then concentrated in vacuo. Chromatography on silica gel (isohexane:isopropanol 4:1) gave the title compound (70 mg).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.O1CCCC1>[C:15]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1)#[N:16]
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1Br
Reactant: N#C[Cu]C#N
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Temperature: 200 °C

Procedure:
To a solution of 4-bromo-2,5-dimethylbenzenesulfonamide (4.6 g, 22 mmol, the product of Step A) in N-methylpyrrolidinone (30 mL) was added copper cyanide (2.5 g, 28 mmol), and the reaction mixture was heated at 200° C. for 30 min. The reaction was then allowed to cool and poured into 200 mL of crushed ice to precipitate a solid. To this mixture was added dichloromethane (500 mL), and the mixture was warmed to dissolve the white solid. The mixture was then filtered to remove any undissolved solids, the phases were separated, and the dichloromethane was washed with water (2×100 mL), dried over magnesium sulfate, and evaporated under reduced pressure to obtain an oil. The oil was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and the solution was concentrated under reduced pressure to precipitate a solid. This solid was isolated by filtration and washed with water to afford 2.5 g of the title compound. 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.56 (s, 1H), 4.89 (br s, 2H), 2.66 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:24][CH2:23][CH2:21][OH:22])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: COc1ccc2c(Cl)cc(-c3ccc(C)cc3)nc2c1
Product: COc1ccc2c(NCCO)cc(-c3ccc(C)cc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 254-255° C. and MS: m/e=309.2 (M+H+), was prepared from 4-chloro-7-methoxy-2-p-tolyl-quinoline and ethanolamine.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][N:15]2[N:43]=[C:19]3[CH2:20][C:21](=O)[C:22]4[CH2:23][S:24][N:25]=[C:26]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:17]([C:18]=43)=[N:16]2)[C:8]=1[CH3:44].O1CCCC1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]([NH:4][CH:21]1[C:22]2[CH2:23][S:24][N:25]=[C:26]([NH2:27])[C:17]3=[N:16][N:15]([CH2:14][C:9]4[C:8]([CH3:44])=[C:7]([O:6][CH3:5])[C:12]([CH3:13])=[CH:11][N:10]=4)[N:43]=[C:19]([C:18]=23)[CH2:20]1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2N=C3CC(NC(C)C)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Isopropylamine (5.5 μl) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (30 mg), methanol (0.4 ml), tetrahydrofuran (0.2 ml) and acetic acid (12 μl), and then the mixture was stirred at room temperature for two hours. A solution of sodium cyanoborohydride (10 mg) in methanol (0.4 ml) was added to the reaction mixture, followed by stirring at room temperature overnight. The reaction mixture was concentrated, and a 0.2 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (1 ml) and trifluoroacetic acid (0.25 ml) were added to the resulting residue, and the mixture was stirred at room temperature for five hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (chloroform-methanol). The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (6.3 mg, 29%) as an amorphous.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1.[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[CH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[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>[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[C:29][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a mixture of anhydrous THF and triethylamine (24 mL, 2/1, v/v) were sequentially added 1,4-diiodobenzene (2.03 g, 6.15 mmol) and copper (I) iodide (0.094 g, 0.246 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.173 g, 0.246 mmol) was added into the mixture under Argon protection. The other starting material, but-3-ynylcarbamic acid benzyl ester (0.50 g, 2.46 mmol), dissolved in THF (8 mL) was added dropwise over 6 hours. The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-12%) and hexanes (100-88%) to afford the product 22 (0.852 g, 86%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 2.61 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 5.07 (br s, 1H), 5.12 (s, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.35 (m, 5H), 7.63 (d, J=8.3 Hz, 2H). m/z (APCI) 405 [C18H16NO2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:26](=[O:29])([O-])[O-].[K+].[K+].[CH:32]([NH:35][CH2:36]CO)([CH3:34])[CH3:33]>CN(C)C=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:26][OH:29])=[CH:18][C:17]=3[CH2:36][NH:35][CH:32]([CH3:34])[CH3:33])[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NCCO
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NCc1cc(CCO)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
380 mg (1 mMol) of trans-N-(4-chlorobenzoyl)-N-methyl-4-(4-chloromethylphenyl)cyclohexylamine are reacted with 280 mg (2 mMol) of potassium carbonate and 110 mg (1.07 mMol) of 2-isopropylaminoethanol in 3 ml of dimethylformamide as described in Example 1. 259 mg (58.5% of theory) of the title compound are obtained in the form of colourless crystals, melting point 98°-100° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:21]([O:24][C:25]1[C:26](=O)[C:27](=[O:33])[C:28]=1[O:29]C(C)C)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CO>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@H:3]([NH:2][C:26]2[C:27](=[O:33])[C:28](=[O:29])[C:25]=2[O:24][CH:21]([CH3:23])[CH3:22])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)Nc1c(OC(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of methyl (2S)-2-amino-3-(4-biphenylyl)-propanoate hydrochloride (415 mg, 1142 mmol),3,4-diisopropoxy-3-cyclobutene-1,2-dione (281 mg, 1.42 mmol), DIPEA (247 μl, 1.42 mmol) and MeOH (10 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by column chromatography (SiO2; DCM/MeOH, 98:2) to give the title compound (358 mg). δH (DMSO-d6, 390K) 8.50 (1H, d, J 8.0 Hz), 7.63-7.56 (4H, m), 7.47-7.42 (2H, m), 7.36-7.32 (3H, m), 5.24-5.18 (1H, m), 4.80-4.75 (1H, m), 3.74 (3H, s), 3.31 (1H, dd, J 14.2, 5.2 Hz), 3.13 (1H, dd, J, 14.2, 9.4 Hz), 1.38 (3H, d, J 6.0 Hz), 1.37 (3H, d, J 6.1 Hz); m/z (ES+, 70 V) 394 (MH+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[C:20]([NH:22][NH2:23])=[O:21])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([C:20]2[O:21][C:1](=[O:2])[NH:23][N:22]=2)[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Yield: 51.7 %

Procedure:
1,1'-Carbonyl diimidazole (0.8 g, 0.005 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazide (1.0 g, 0.004 mole) and triethylamine (0.6 ml, 0.004 mole) in tetrahydrofuran (12 ml). After 18 hours the mixture is concentrated in vacuo and the residue dissolved in ether. The solution Is washed with aqueous 2M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO 4. Filtered and concentrated in vacuo to obtain a residue which is purified by flash chromatography using 10% ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane to obtain 0.6 g (1.1 g theor., 55%) 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one, mp 246° C.