Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].C([Li])CCC.[CH2:16]=[O:17]>C1COCC1>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:16][OH:17])([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Br
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccccc1CO
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 1-bromo-2-isopropylbenzene (2.50 g, 12.56 mmol) in anhydrous THF (40 mL), 2,2′-dipyridyl (ca 2 mg) was added under nitrogen atmosphere (Zhi et al., 2003, which is incorporated herein by reference). The mixture was cooled down minus 78° C., and a solution of n-butyllithium (5.52 mL, 2.5 M in hexanes, 13.82 mmol) was added dropwise via syringe within the period of ten minutes. Upon addition, the mixture was stirred for 30 minutes, then warmed up to minus 30° C., and a flow of formaldehyde (generated from 1.77 g of paraformaldehyde by heating at 160° C.) was passed through the solution until the deep red color disappeared completely. The mixture was quenched with saturated ammonium chloride (5 mL), then poured into brine (15 mL). Organic layer was separated; aqueous layer was extracted twice with dichloromethane (20 mL each); combined extracts were dried over anhydrous Na2SO4, evaporated, and purified by silica gel chromatography to yield 2-isopropylbenzyl alcohol (1.11 g, 59%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.30 (m, 3H, Ph-H), 7.18 (m, 3H, Ph-H), 4.75 (s, 2H, CH2OH), 3.27 (sep, J=6.6 Hz, 1H, CH(CH3)2), 1.53 (s, 1H, CH2OH), 1.26 (d, J=6.6 Hz, 1H, CH(CH3)2).
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:20][CH:21]([C:29]([F:32])([F:31])[F:30])[C:22]([F:28])([F:27])[S:23]([O-:26])(=[O:25])=[O:24].[C:33]1([S+:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:28][C:22]([F:27])([S:23]([O-:26])(=[O:24])=[O:25])[CH:21]([O:20][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH2:14]3)[CH2:8]1)[CH2:10]2)=[O:18])[C:29]([F:30])([F:32])[F:31].[C:46]1([S+:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])(C3)C2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 28.4 g (0.10 mole) of the resulting 3-methacryloyloxyadamantanecarbonyl chloride were added 44.9 g (0.09 mole) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 10.1 g (0.10 mole) of triethylamine and 2.2 g (0.02 mole) of N,N-dimethylaminopyridiene in 45 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 7 hours. Thereafter, 105 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 250 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. Diisopropyl ether was added to the residue, followed by decantation. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(3-methacryloyloxy-adamantane-1-carbonyloxy)-propane-1-sulfonate was obtained as brown oil (61.7 g, yield 92%). The compound has the following structure.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][N:12]=[C:11]2[S:16][CH3:17])=O.Cl.[CH:27]1([NH:32][C:33]([NH2:35])=[NH:34])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:27]1([NH:32][C:33]2[N:35]=[C:5]([C:7]3[C:8]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][N:12]=[C:11]4[S:16][CH3:17])[CH:4]=[CH:3][N:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N=C(N)NC1CCCC1
Reactant: CSc1nccc2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (660 mg, 1.85 mmol) and N-cyclopentylguanidine hydrochloride (600 mg, 3.71 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (760 mg, 5.55 mmol). The reaction mixture was heated to 100° C. for 1 hour and then to 115° C. for 4 hours. The reaction was allowed to cool to room temperature and diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography eluting with 50% acetone in dichloromethane to yield N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (210 mg, 32%). 1H NMR (CDCl3): δ 8.05(d,1H), 7.94 (m, 2H), 7.64 (dd, 2H), 7.13 (t, 2H), 6.29 (d, 1H), 5.21 (bs, 1H), 4.31 (m, 1H), 2.72 (s, 3H), 2.06 (m, 2H), 1.49–1.82 (m, 6H). MS m/z 421 (M+1).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:10].NC(N)=O>[N+]([O-])(O)=O>[Cl:10][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: NC(N)=O
Solvent: O=[N+]([O-])O
Product: CC(C)C[C@H](Cl)C(=O)O
Temperature: 80 °C

Procedure:
L-(+)-Leucine (10 g, 0.076 moles) is mixed with 24 mL of concentrated HCl and 10 mL of concentrated HNO3 with the addition of 2 g of urea and subsequently heated for 1 hour at 80° C. and then for 1 hour at 50° C. on a water bath (complete dissolution of the acid with heavy foaming). After cooling, the solution is extracted with ether several times, the ether extract is washed with water and dried over calcium chloride, the solvent is distilled off in a rotary evaporator and the residue is fractionally distilled under vacuum.
Reaction SMILES: C(OCC)(=O)CC(C)=O.C(O)(=O)C(O)=O.NN.[CH:18]1([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][C:22]=2[CH:29]=[O:30])CC1>>[CH:26]1([N:25]2[C:21]([CH3:18])=[C:22]([CH:29]=[O:30])[CH:23]=[N:24]2)[CH2:27][CH2:28]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C1CC1

Procedure:
1-Cyclopropyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl acetoacetate and cylclopropyl hydrazine oxalate (Gever, G. and Hayes, K. J. Org. Chem, 1949, 14, 813–818) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C(Cl)Cl>[C:15]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: OC1CCSCC1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCSCC1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To a 200-mL three-necked flask fitted with a stirrer bar coated with Teflon™, were added 5.37 g of 4-hydroxytetrahydrothiopyran (manufactured by SANKYO KASEI Co., Ltd.), 5.08 g of triethyl amine, and 50 mL of dried methylene chloride, and the mixture was stirred under nitrogen atmosphere at 0° C. To the mixture, 5.0 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulted mixture was reacted at 0° C. for 40 minutes, allowed to warm to room temperature, and was further reacted for another 5 hours. After confirming loss of the starting material by a thin layer chromatography (TLC), the reaction solution was poured into a 300-mL separatory funnel, washed with 100 mL of water followed by 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to give 5.18 g of tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 2) (yield: 61.3%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC)(=O)CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:37][CH3:38])[C:33]([O:35][CH3:36])=[O:34]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:37]([CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:33]([O:35][CH3:36])=[O:34])[CH3:38]
Reactant: CCC(CCCCBr)C(=O)OC
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCC(=O)OC
Product: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)OC
Temperature: 100 °C
Reaction time: 40 h

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (2.8 g) (prepared by analogy with the method described in Patent EP 108 592 from methyl butanoate), methyl 6-bromo-2-ethylhexanoate (5.4. g), silver carbonate (1.6 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 31 hours then at 120° C. for 40 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil)
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 37 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.7 eq) of sodium hydroxide and 460 mg (1.05 mmol, 1 eq) of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from a dichloromethane/pentane mixture, 160 mg of (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylic acid are obtained in the form of a white powder. (m.p.=159° C.). Yield=37%
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Yield: 97.2 %

Procedure:
A solution of ethyl 4-(4-phenylphenyl)butanoate (21.0 g) and potassium hydroxide (9.65 g) in ethanol (50 ml) and water (50 ml) was heated under reflux for 2 hours. The resulting mixture was allowed to cool, diluted with water (150 ml), washed with ether (x2), acidified with concentrated hydrochloric acid, and extracted with ether. The extracts were washed with water, dried and concentrated to give crude 4-(4-phenylphenyl)butanoic acid [(3), 18.28 g] as a white solid, m.p. 111°-113° C. (D. H. Hey and R. Wilkinson, J. Chem. Soc., 1940, 1030, give a m.p. of 118°-119° C. for this acid).
Reaction SMILES: COC(OC(OC)=O)=O.[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[OH:30])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccccc1
Reactant: Oc1ccccc1
Agent: COC(=O)OC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(c1ccccc1)c1ccccc1O

Procedure:
A stock solution containing 6 wt% DMPC, 15 wt% cumene and 50 ppm sulfuric acid with the balance composed of equimolar phenol and acetone was distributed among several melting point capillary tubes which were subsequently sealed and heated for various lengths of time in a stirred oil bath. The tubes were then quickly cooled by immersion in an ice bath and the contents were analyzed by gas chromatography. The amount of AMS formed increased with time up to a maximum yield and then declined as increased amounts of AMS dimers and cumylphenol were formed. Table II records the maximum AMS yield obtained at each temperature, as well as the heating time required to reach that yield. It is clear from the data of Table II that the best yields of AMS were obtained at temperatures over 90° C., e.g., 120° and 130° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=O>CN(C1C=CN=CC=1)C.ClCCl>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:16][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:9]
Reactant: N[C@H](c1ccccc1)[C@H](N)c1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N[C@H](c1ccccc1)[C@H](NCc1ccccn1)c1ccccc1
Yield: 71 %

Procedure:
A solution of (1R,2R)-1,2-diphenylethylenediamine (1.16 g, 4.74 mmol), picolinic acid (596 mg, 4.79 mmol, 1.01 eq.), N,N-dimethyl-4-aminopyridine (100 mg, 0.82 mmol, 0.17 eq.) and 1,3-dicyclohexycarbodiimide (1.07 g, 5.2 mmol, 1.1 eq.) in dichloromethane (40 ml) was stirred at room temperature under N2 for 18 hours. The reaction mixture was filtered and washed with water. Column chromatography on silica gel using EtOAc/CH2Cl2 (4:1) afforded 1.06 g of white solids as title compound (71% yield). NMR and GCMS confirmed the structure.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16](O)=[O:17])=[C:9]([Cl:13])[C:10]=2[Cl:12])[CH2:5][CH2:4][CH:3]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C1C=CC=CC=1>[CH2:29]([N:31]([CH2:32][CH3:33])[C:16](=[O:17])[CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([Cl:12])[C:9]=1[Cl:13])[C:2](=[O:1])[CH:3]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:4][CH2:5]2)[CH3:30]
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reactant: CCNCC
Agent: Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reaction time: 1 h

Procedure:
The product of Example I, Step 5 (4.0 g., 0.02 mole) is added to thionyl chloride (11 g.) and the mixture is refluxed until HCl and SO2 are no longer evolved (about 1 hour). The excess thionyl chloride is evaporated. The residue is dissolved in benzene and a solution of diethylamine (3.6 g., 0.05 mole) in benzene is added. The mixture is kept for 1 hour and then evaporated to dryness. The residue is washed with water, 10% sodium bicarbonate and with water and airdried to obtain N,N-diethyl-(1-oxo-2-cyclopentyl-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)acetamide.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:6][C:7]4[CH:8]=[C:9]5[C:13](=[CH:14][CH:15]=4)[NH:12][CH:11]=[CH:10]5)[C:38]=3[CH:37]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Temperature: 137.5 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
After adding 1.9 ml of dimethylformamide, 180 mg of 5-hydroxyindole and 112 mg of potassium carbonate to 190 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 135-140° C. for 4 hours. After returning it to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 90 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[C:27]([O:34][C:35](=[O:41])[C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])[CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOS(C)(=O)=O)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)C(=O)Oc1cccc2ccc(OCCOc3ccc(C(=O)C(=O)OC)cc3)cc12
Temperature: 60 °C
Yield: 40.4 %

Procedure:
To a stirred suspension of sodium hydride (55% dispersion in mineral oil, 0.105 g) in dimethylformamide (5 mL) was added dropwise a solution of 4-hydroxy-alpha-oxobenzene acetic acid methyl ester (0.432 g) in dimethylformamide (5 mL) under argon. The mixture was then treated dropwise with a solution of 2-[8-(2,2-dimethyl-1-oxobutoxy)-2naphthalenyloxy]ethyl methanesulfonate (0.76 g) in dimethylformamide (5 mL). The reaction was heated for 18 hours at 60° C., diluted with brine, and extracted with ethyl acetate. After evaporation of volatiles, the residue was purified by chromatography over silica gel (hexane-ethyl acetate; 10: 1) to yield 0.375 g of 4-[[2-[8-(2,2-dimethyl-1-oxobutoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a white solid, mp 119°-120° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[N:18]1([C:14]([C:10]2[S:9][C:8]([Br:7])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Br)sc1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Oxalyl chloride (0.47 mL; 5.41 mmol) was added to a solution of 2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid (1.0 g; 4.5 mmol) in DCM (25 mL). The mixture was stirred at RT for 18 hours, the DCM was evaporated in vacuo, the residue azeotroped with toluene (2×5 mL) and added to a solution of azetidine hydrochloride (503 mg; 5.41 mmol) and triethylamine (2.3 mL; 16.2 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give a solid which was crystallised from ethyl acetate/isohexane to give the desired compound (490 mg). 1H NMR δ (CDCl3): 2.35 (m, 2H), 2.55 (s, 3H) and 4.1 (t, 4H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:26]([NH:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:27]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: Cc1ccc(CNC(=O)C(C)C(=O)O)cc1
Product: Cc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-methyl-benzyl)-malonamic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1.C([BH3-])#N.C(O)(=O)C>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=Cc1cccs1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A mixture of thiophene-2-carbaldehyde (0.021 mL, 0.22 mmol), 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (40 mg, 0.22 mmol), and siliabond cyanoborohydride (240 mg, 0.24 mmol, 1 mmol/g) in ethanol (1 mL) was stirred at ambient temperature for 10 minutes. Acetic acid (0.013 mL, 0.22 mmol) was then added, and the mixture was stirred at ambient temperature for another 5 minutes. The reaction mixture was concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 10:90) to provide the title compound (30 mg, 49% yield). m/z 278.1 (M+1), retention time=0.89 min.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1SC.[CH3:15][NH:16][CH3:17]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:11][CH3:12])[CH3:10])=[N:5][N:4]=[C:3]1[N:16]([CH3:17])[CH3:15]
Reactant: CNC
Reactant: CCC(C)c1nnc(SC)n(N)c1=O
Product: CCC(C)c1nnc(N(C)C)n(N)c1=O
Yield: 93 %

Procedure:
Analogously to the procedure described in Example 5, reaction of 42.8 g of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5 (4H)-one with dimethylamine gave 39.4 g (93% of theory) of 4-amino-6-sec.-butyl-3-dimethylamino-1,2,4-triazin-5 (4H)-one in the form of a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1.[C:22](Cl)(=[O:24])[CH3:23]>C(OCC)(=O)C.CCCCCC>[C:22]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: N#Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2cccc(C#N)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-cyanobenzoyl)indole (Example 127) and acetyl chloride. m.p.: 185-187° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 11.91 (1H, br s), 9.85 (1H, brs), 8.12-8.04 (2H, m), 8.03-7.95 (1H, m), 7.77-7.62 (2H, m), 7.46 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=1.8, 8.8 Hz), 1.64 (3H, s)