Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1COCC1.O.[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:44][CH:45]=1.O>C(#N)C>[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([S:46]([O-:49])(=[O:48])=[O:47])=[CH:44][CH:45]=1.[C:28]([CH:26]1[CH2:27][NH+:24]([CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[S:16][C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][N:14]=3)[C:18]=2[CH2:31][CH3:32])[CH2:25]1)([OH:30])=[O:29]
Reactant: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CCc1c(C[NH+]2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (50 mg, 0.106 mmol) was added to a mixture of THF (1 mL), water (0.6 mL) and ACN (2 mL), a suspension was obtained to which was added p-TsOH.H2O (24.26 mg, 0.117 mmol). A solution was obtained and stirred for 30 min at rt. Solvent was removed under the reduced pressure and dried in vacuum to give 3-carboxy-1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidin-1-ium 4-methylbenzenesulfonate (65 mg) as pale yellow oil.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OCC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][C:20]1[O:1][N:2]=[C:3]([CH:5]2[CH2:7][CH2:6]2)[N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: N=C(NO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nc(C2CC2)no1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
3.10 g (30.96 mmol) N-hydroxy-cyclopropanecarboxamidine are placed in 10 ml dimethylformamide and molecular sieve. 1.32 g (34.06 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 7.40 g (34.06 mmol) ethyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21]3)=[C:13]([NH2:29])[N:12]=2)[CH:10]=1)=O)C.[CH3:30][NH2:31]>>[OH:25][C@@H:24]1[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([NH:31][CH3:30])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH2:29]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 65 °C

Procedure:
Compound 12 (0.05 mg, 0.12 mmol) was added to 4 mL methylamine (40% sol. In water). The mixture heated at 65° C. in for 24 h. After concentration in vacuo, the residue was purified using prep. TLC (10% MeOH:DCM). 1HNMR (CD3OD) δ 2.90 (s, 3H), 3.78 (m, 1H), 3.91 (m, 1H), 4.13 (d, 1H), 4.34 (d, 1H), 4.64 (m, 1H), 6.06 (d, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:4]1=[O:23].C(N(C(C)C)C(C)C)C.C[N:34](C)[CH:35]=[O:36]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([NH:2][C:35]([NH2:34])=[O:36])[C:4]2=[O:23])=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: N[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 250 mg (0.7 mmol) of (R)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride and 294 mg (2.2 mmol) of N-ethyl-diisopropylamine in 2 ml of N,N-dimethylformamide is cooled to 0° C. and treated with 267 mg (2.2 mol) of trimethylisocyanate. The reaction mixture is left to warm to RT and stirring is continued for 2 days. For the working-up, the suspension is evaporated under reduced pressure. The crude product is triturated in water, then the recovered solid material triturated a second time in a mixture of ethyl acetate and a saturated solution of sodium hydrogencarbonate. The remaining solid is collected on a filter funnel to give, after drying under high vacuum, 155 mg (61% of theory) of (R)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-urea as a white solid; MS: m/e=344 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[C:19]1(=[CH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[C:19]1([CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:20]1
Reactant: COC(=O)C=C1CC1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(CC(=O)OC)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
240 ml (1.70 mol) of diisopropylamine were dissolved in 700 ml of abs. THF, the mixture was cooled to −40° C. and 681 ml (1.7 mol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The solution was stirred at −40° C. for 30 min and then cooled to −78° C., and a solution of 166.6 ml (1.7 mol) of ethyl acetate p.a. in 200 ml of abs. THF was added. After the end of the addition, the mixture was stirred at −78° C. for another 30 min 159 g (crude product, about 1.42 mol) of methyl cyclopropylideneacetate, dissolved in a little abs. THF, were then added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then, via −40° C., slowly warmed to about 0° C., and a saturated aqueous ammonium chloride solution was finally added. The mixture was extracted with ethyl acetate and the organic phase was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 9:1). This gave 109.5 g of the target compound which was contaminated by the diethyl ester derivative and was not purified any further.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([CH2:10][CH2:11][CH:12]=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:14][N:15]1[CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]1[CH3:22].Cl>O.CO>[CH3:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[N:15]1[NH:14][CH:12]([CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: O=CCCc1ccccc1
Reactant: [C-]#N
Reactant: CC1CCCC(C)N1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCCC(C)N1NC(C#N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 106.7 %

Procedure:
A solution of 5.4 g of sodium cyanide in 20 ml of water and a solution of 14.7 g of 3-phenylpropionaldehyde in 15 ml of methanol are added dropwise with ice-cooling to a mixture of 12.8 g of 1-amino-2,6-dimethylpiperidine, 60 ml of water and 9.4 ml of concentrated hydrochloric acid. The pH is adjusted to 7 with hydrochloric acid and the reaction mixture is stirred at room temperature for 3 days. The mixture is extracted with dichloromethane, and the combined extracts are washed with water of pH 4 containing hydrochloric acid, dried and concentrated in a rotary evaporator. 28.9 g of 2-((2,6-dimethylpiperidino)amino)-4-phenylbutyronitrile are obtained, which are employed in the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24](N2CC[C@@H](OS(C)(=O)=O)C2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:22]=[CH:23][C:24]([N:37]2[CH2:41][CH2:40][C@H:39]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:38]2)=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](OS(C)(=O)=O)C3)cc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@H](N4CCCC4)C3)cc2)C1
Temperature: 90 °C
Yield: 58.3 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-methansulfonyloxy-pyrrolidino)phenyl)piperazine (877 mg, 1.64 mmol) in toluene (10 mL) was added pyrrolidine (0.64 mL, 8.19 mmol), and the resulting solution was heated at 90° C. for 8 h. After checking consumption of the starting material with TLC, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 30-100% ethyl acetate-hexane and then 3-10% methanol-ethyl acetate to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazine (479 mg, 58%) as a pale yellow powder.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O

Procedure:
19-Hydroxy-4-androstene-3,17-dione and chloranil are dissolved in t-butanol which is rapidly brought to its reflux temperature. The t-butanol is removed by distillation at atmospheric pressure at such a rate that the combined reflux and distillation time equals one hour. The dark pasty residue is triturated with hot chloroform and cooled. The solid is removed by filtration and the filtrate extracted with water, a 2% sodium hydroxide solution and again with water. The organic layer is dried over magnesium sulfate and the solvent removed under vacuum to yield 19-hydroxy-4,6-androstadiene-3,17-dione. This diene so prepared is dissolved in acetone and chilled in an ice bath. Jones reagent is added over a 10 minute period and stirring continued for an additional 45 minutes. The mixture is poured onto water. The solid is filtered and recrystallized from benzene to yield 4,6-androstadiene-3,17,19-trione.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=C[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][CH:7]=1)=[O:5].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.[CH2:25]([Cl:27])Cl>>[NH2:17][C:18]1[C:19]([NH:1][C:2]2[CH:16]=[C:25]([Cl:27])[CH:14]=[CH:13][C:3]=2[C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1cc(Cl)ccc1C(=O)c1ccccc1
Temperature: 180 °C

Procedure:
A stirred mixture of 23.2 g (0.1 mole) of 2-amino-4'-chlorobenzophenone and 14.2 g (0.11 mole) of 3-amino-2-chloropyridine was heated at 180° C. under nitrogen atmosphere for 2.5 hr. The mixture solidified upon cooling to room temperature and was broken up with a spatula. The solid was suspended in 100 ml of methylene chloride and collected by filtration. The filter cake was dissolved in a mixture of water-methanol, basified with 3N sodium hydroxide and extracted twice with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue which had crystallized was triturated in isopropyl ether and the solid (16.7 g) collected by filtration. A 3 g sample was recrystallized from isopropyl ether to give 1.6 g product; m.p. 153°-155° C.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.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>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:16]2[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(-c2cccn2C)cc1C=O
Yield: 46 %

Procedure:
Ex-44A: A solution of 5-bromo-2,4-dimethoxybenzaldehyde (1.90 g, 7.77 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) in dioxane (150 mL) was treated with 1-methyl-2-(tributylstannyl)-1H-pyrrole and then refluxed for 68 h. The reaction mixture was quenched with 10% potassium fluoride/ether (300 mL/100 mL) and filtered through Celite. The organic phase was extracted with saturated ammonium chloride solution (4×25 mL), dried over magnesium sulfate, and concentrated to a brown solid. The solid was purified by column chromatography (30% ethyl acetate/hexane) to yield 0.87 g (46%) of 2,4-dimethoxy-5-(1-methyl-1H-pyrrol-2-yl)benzaldehyde as a white solid. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1 H), 7.78 (s, 1H), 6.72 (m, 1H), 6.51 (s, 1H), 6.20 (m, 1H), 6.13 (m, 1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]2=O)=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@@H:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@H:19]2[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CCC(N)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 7 %

Procedure:
1-Ethylpropylamine (124 μL, 1.06 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (197 mg, 0.531 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. Methanol (3 mL) was added to the reaction solution. Sodium cyanoborohydride (100 mg, 1.59 mmol) and acetic acid (304 μL, 5.31 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 49 mg of the cis isomer of the title compound (21%) as a pale yellow oily substance and 16 mg of the trans isomer of the title compound (7%) as a pale yellow oily substance.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH2:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH:26][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[CH:20]=[CH:21][C:22]=1[OH:23]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N)c2nc(CNCCc3ccc(O)c(O)c3)cnc2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (67.3 mg, 0.2003 mmol) in anhydrous N,N dimethylacetamide was added 2-(3,4-dihydroxyphenyl) ethylamine (43.6 mg, 0.23 mmol). Under positive pressure of Argon, iPr2EtN (32.63 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 14.8 mg product was obtained. Yield: 22.6%; 1H NMR (500 MHz, DMSO-d6): δ 2.69242 (b, 4H), 4.03353 (s, 2H), 6.37542–6.39065 (d, J=7.615 Hz, 1H), 6.4851(s, 1H), 6.56632–6.58226 (d, J=7.97 Hz, 1H), 8.80972 (s, 1H); ESI-MS: m/z 328 (M++1)
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([Si:9]([CH3:32])([CH3:31])[O:10][C@H:11]([C:24]1[CH:25]=[N:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:8])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CS(C)=O>[C:5]([Si:9]([CH3:31])([CH3:32])[O:10][CH:11]([C:24]1[CH:25]=[N:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:12][NH:4][CH2:3][CH2:1][OH:2])([CH3:6])([CH3:7])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Reactant: NCCO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC(CNCCO)c1ccc(Cl)nc1

Procedure:
A solution of ethanolamine (1.2 mL), (R)-toluene-4-sulfonic acid 2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl ester (2.2 g) and diisopropylethylamine (1.3 mL) in DMSO (5 mL) was heated at 80° C. for 4 h. After cooling, the reaction solution was diluted into ethyl acetate, washed with water (2×), brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-3a) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p. 131° C. and MS: m/e=383 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromo-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1[CH:14]=[CH:13]C=CC=1.C(OC(=O)C)(=[O:17])C>>[CH2:3]([CH2:2][C:1]([NH2:8])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:13][CH3:14]
Reactant: CCCCCCCN
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: CCCCCCCCC(N)=O
Reaction time: 2 h
Yield: 96 %

Procedure:
Heptylamine (39 g; 0.34 mole was added dropwise to 46.6 g (0.59 mole) of pyridine and 43.4 g (0.43 mole) of acetic anhydride over 30 minutes, and the mixture was further stirred for 2 hours. After the reaction, the mixture was concentrated and extracted by adding water and ether. The ethereal layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and then a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate and concentrated to give 51 g of the desired compound yield 96 %).
Reaction SMILES: [CH3:1][C@@:2]1(O)[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C
Temperature: 25 °C

Procedure:
A solution of 1 g (3.7 mmol) of methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (VII) in 90 ml of anhydrous benzene was treated with 2.75 ml of freshly distilled thionyl chloride and heated under reflux for 2 hours. The reaction mixture, after being cooled to room temperature, was washed with water and then treated under stirring with an aqueous solution of sodium hydrogen carbonate. The organic phase was separated off, washed with water and evaporated under vacuum to dryness to give compound (VIII), 0.82 g, 87% as a white solid; m.p. 160°-162° C., [α]D20° -180° (c=1, CHCl3). The PMR spectrum (CDCl3) showed absorptions at 1.35 (d, CH3 --C--5), 3.37 (s, CH3O), 4.37 (q, H--C--5), 4.83 (broad s, CH2 =C--4) and 4.95 δ (broad s, C--1--H).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[C:5]([O-])(=O)C.[C:9]([O-:12])(=[O:11])[CH3:10].[C:13]([O-:16])(=O)[CH3:14].[Pb+4].[CH:18]1C=CC=CC=1.C(O)(=O)C=O>O>[CH:1](=[O:4])[CH2:2][CH3:5].[CH:13](/[C:14](/[CH3:18])=[CH:10]\[C:9]([OH:12])=[O:11])=[O:16]
Reactant: CC(=O)[O-]
Reactant: c1ccccc1
Agent: O=CC(=O)O
Agent: [Pb+4]
Solvent: O
Product: C/C(C=O)=C/C(=O)O
Product: CCC=O

Procedure:
Compounds of formula III where n is zero and B is an oxo group can be prepared, for example, by oxidatively cleaving an optionally esterified tartaric acid; for example, using lead tetraacetate at room temperature in an organic solvent such as benzene. The resulting glyoxalic acid derivative is subsequently condensed in a conventional manner, e.g., conveniently in the presence of an amine, with propionaldehyde at an elevated temperature, e.g., at a temperature between 60° C. and 110° C. with water cleavage to yield the corresponding 3-formyl-crotonic acid derivative.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CN(C=O)C.[CH2:27]([N:29]1[C:35](=[O:36])[C:34]([CH3:38])([CH3:37])[C:33](=[O:39])[N:32]([CH3:40])[C:31]2[CH:41]=[C:42]([OH:45])[CH:43]=[CH:44][C:30]1=2)[CH3:28]>C(OCC)(=O)C.O>[O:21]=[C:12]1[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][CH2:9][CH2:8][O:45][C:42]1[CH:43]=[CH:44][C:30]2[N:29]([CH2:27][CH3:28])[C:35](=[O:36])[C:34]([CH3:37])([CH3:38])[C:33](=[O:39])[N:32]([CH3:40])[C:31]=2[CH:41]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Potassium carbonate (2.99 g, 21.6 mmol) and N-(3-bromopropyl)phthalimide (2.32 g, 8.65 mmol) were added to a DMF solution (50 ml) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.89 g, 7.2 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→3:7). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.70 g (yield: 83%) of 7-(3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder.