Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
2.00 g (9.94 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were dissolved in 50 mL of DMF. To this solution, 2.07 g (10.94 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich®, cat. no. 13, 451-1) and 2.10 g (10.95 mmol) of EDC.HCl were added and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum, the residue was taken up in ethyl acetate and the organic solution was washed with an aqueous solution of sodium bicarbonate and brine, it was dried over magnesium sulphate, filtered and the solvent was evaporated. The product was purified by flash chromatography (0-5% methanol in dichloromethane). 2.21 g (60% yield) of the final product were obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[NH:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:14]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(CNC(=O)OC(C)(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-(tert-butoxycarbonylamino-methyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.03 min; [M+H]+=506.46.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1)=[N+]=[N-].ClCCl>CO.CN(C)C=O.[Pd]>[NH2:1][CH2:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@@H]1CC[C@H](C(=O)O)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: NC[C@@H]1CC[C@H](C(=O)O)C1

Procedure:
A mixture of cis-3-azidomethylcyclopentancarboxylic acid (0.9 g, 5.3 mmol) in methanol (about 30 mL) was hydrogenated at about 50 psi and room temperature in the presence of 10% Pd on carbon (about 40 mg) for about 1 h. The catalyst was removed by filtration and the filtrate concentrated to give a syrup. When the syrup was dissolved in dimethylformamide and dichloromethane for acetylation (next step), formation of some white precipitate occurred. The precipitate was collected by filtration, washed with dichloromethane and dried to give cis-3-aminomethylcyclopentanecarboxylic acid as a white powder, mp 186-188° C. The yield of syrup was 0.7 g (100%). The white solid obtained was about 0.35 g. The remainder of the material from the dimethylformamide and dichloromethane mixture was not recovered, but was used for the acetylation step.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[S:12][C:11](Br)=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C([Li])CCC.O>C1COCC1>[CH2:1]([NH:4][S:5]([C:8]1[S:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])[CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)c(Br)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
N-(5-{5-[(allylamino)sulfonyl]-2-bromo-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide obtained in Step I as described above (35 mg; 0.08 mmol; 1 eq), is dissolved in dry THF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.18 ml; 1 M; 0.18 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 1 hour before being hydrolyzed with water (0.3 ml). Reaction is warmed up to room temperature before being concentrated to dryness. Residue is taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Title compound is purified by reverse preparative HPLC, affording Compound (49) as a white powder (3 mg; 10%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Product: COc1ccc(CNCC2=C3C(=O)N=C(N)N=C3N=C2)cc1

Procedure:
By the same procedure as Example 5, 162 mg of the above-identified compound is synthesized from 252 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 157 mg of p-methoxybenzyl chloride.
Reaction SMILES: [OH2:1].[OH-].[K+].Cl[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]>C(O)C>[CH3:10][N:9]1[C:5]([OH:1])=[C:6]([C:12](=[O:21])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7]([CH3:11])=[N:8]1
Reactant: O
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(O)c1C(=O)c1c(Cl)cccc1Cl
Yield: 48 %

Procedure:
In 5 ml. of water is dissolved 0.56 g. of potassium hydroxide and a solution of 1.52 g. of 5-chloro-4-(2,6-dichlorobenzoyl)-1,3-dimethylpyrazole in 10 ml. of ethanol is added thereto. The mixture is heated under reflux for 12 hours. After completion of the reaction, the reaction mixture is allowed to cool and extracted with benzene. An aqueous layer is separated and 2N HCl solution is added to adjust the pH to 3-4, whereby crystalline substance is separated out. The resulting crystalline substance is recovered by filtration and recrystallized from ethanol to give 0.68 g. of the desired product as colorless needles melting at 249.5°-250.5° C. Yield 48.0%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([CH3:14])([CH3:13])[C:8](=O)[CH2:9][C:10]#[N:11].[OH-:15].[Na+].S(O)(O)(=O)=O.[NH2:22]O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:8]1[CH:9]=[C:10]([NH2:11])[O:15][N:22]=1)([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: COCCOCC(C)(C)C(=O)CC#N
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COCCOCC(C)(C)c1cc(N)on1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
To a stirred solution of 5-(2-methoxy-ethoxy)-4,4-dimethyl-3-oxo-pentanenitrile (3.04 g, 15.27 mmol) and sodium hydroxide (1.31 g, 32.82 mmol) in water (34 mL) is added hydroxylamine sulfate (1.25 g, 7.63 mmol). The reaction mixture is stirred at reflux for 18 h. After this time, the reaction mixture is cooled to room temperature and extracted with ethyl acetate 3 times. The organic layers are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 35.8%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (6H, s), 3.39 (3H, s), 3.50 (2H, s), 3.50-3.57 (2H, m), 3.57-3.62 (2H, m), 3.30-4.50 (2H, br), 5.16 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:18][C:19]1[N:20]=[C:21]([CH2:25][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3cccc(C)n3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]C1C=CC=CC=1.[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][CH2:44][CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:38][C:37]=1[O:53][CH3:54])=O>C1COCC1>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH2:42][NH:43][CH2:44][CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH:40]=[CH:41][C:36]=1[CH:34]=[CH:7][C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=O
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=Cc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Thiophene-2-ylmethyl triphenylphosphonium chloride (4.4 g, 16.3 mmol) was added to THF (50 ml), and PhLi (8.6 g of 19% solution in hexane, 19.6 mmol) was added dropwise thereto in an ice bath. After 20 minutes, 2,2-dimethylpropionic acid 2-[(4-formyl-3-methoxyphenyl)methylamino]ethyl ester (4.0 g, 13.6 mmol) dissolved in THF (15 ml) was added dropwise. The mixture was reacted for 2 hours. The reaction mixture was added to 300 ml of ice water, and the oily matter was subjected to 3 times of extraction with dichloromethane (50 ml). Washing with a saturated saline solution, drying over Na2SO4, and concentration were performed. The residue was purified by silica gel chromatography to give a yellow oily matter (yield: 4.0 g (79.3%)).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH3:15])[C:12]([OH:14])=O.[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH3:15])[C:12]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(Sc1nc2ccccc2s1)C(=O)O
Product: CC(Sc1nc2ccccc2s1)C(=O)N1CCCc2ccccc21
Yield: 34 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)propanoic acid and 1,2,3,4-tetrahydroquinoline to yield 47 as a yellow oil (34%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.38; H, 5.26; N, 7.97; S, 18.08.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([OH:19])CCCCCCC(C)C>C1(C)C=CC=CC=1>[Br:1]/[C:2](=[CH:7]/[C:6]([OH:5])=[O:8])/[C:3]([OH:19])=[O:4]
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: CC(C)CCCCCCCO
Solvent: Cc1ccccc1
Product: O=C(O)/C=C(/Br)C(=O)O
Yield: 260.6 %

Procedure:
Bromomaleic anhydride (19.5 g), isodecanol (69.5 g) p-toluene sulphonic acid (2 g) and toluene (70 ml) were stirred and boiled under reflux below a Dean-Stark trap of volume 15 ml for 2.5 hours. The solution was then cooled with petroleum ether and the petroleum ether solution was washed with water. The solvent and excess isodecanol were distilled under reduced pressure, finally at 100°/0.2 mm of mercury pressure, leaving the bis(isodecyl)ester of bromomaleic acid (56 g) as an oil with an estimated purity by gas chromatography of 96%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13]C(=O)OC(C)(C)C)=[O:6].[ClH:23].O1CCOCC1.C(OCC)C.CCOCC.CCCCCC>O1CCOCC1>[ClH:23].[NH2:13][C@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]([NH:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)NCC(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl {(cis)-2-[(2,2,2-trifluoroethyl)carbamoyl]cyclohexyl}carbamate, I-5a (2.55 g, 7.86 mmol) in Dioxane (10 ml) was added 4 M HCl/Dioxane (19.66 ml, 79 mmol) and the mixture allowed to stir at RT for 60 min. The reaction was concentrated in vacuo and resulting solid slurried with diethyl ether (100 mL). Re-concentration of the mixture and re-slurry of the solid with ether/hexane gave a free flowing solid. Final concentration of the mixture gave a white solid, I-5b, (2.1 gm) which was stored under nitrogen.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[O:11][CH3:12].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:20].[K+].[OH2:25]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([OH:20])=[O:25])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C)cc(OC)c1Cl
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)cc(OC)c1Cl

Procedure:
77.5 G. of 4-chloro-3,5-dimethoxytoluene were dissolved in 1030 ml. of pyridine. The solution was heated to reflux and treated dropwise during 1 hour with a solution of 197 g. of potassium permanganate in 3100 ml. of hot water. The mixture was heated to reflux for an additional 30 minutes. Then, 1700 ml. of a pyridine/water mixture were recovered by distillation. The residue was removed by filtration under suction while hot and, after cooling, the filtrate was acidified with 600 ml. of 10N sulfuric acid. The precipitate was removed by filtration and extracted with ether to recover unreacted starting material, whereby there was obtained 4-chloro-3,5-dimethoxybenzoic acid having a melting point of 247° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](I)[CH3:37].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:36][CH3:37])=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 32) (200 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 25 mg), ethyl iodide (0.052 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (170 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24](Cl)=[O:25])=[CH:19][CH:18]=1.[C-:30]#[N:31].[Na+].O>C1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]([CH3:29])[CH3:28])[C:24]([O:12][CH:11]([C:30]#[N:31])[C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer was charged with 10 mmol of 3-phenoxybenzaldehyde, 10.0 or 10.5 mmol of 2-(4-chlorophenyl)-3-methylbutanoyl chloride, 12 mmol of sodium cyanide, 0.02 ml of water and 20 ml of an aprotic solvent. The molar ratio of water to sodium cyanide was 0.105, solid NaCN being present. Thirteen experiments were conducted in this manner, see Table IV, stating which solvents were used. Experiments 1, 2, 3, 4, 8 and 9 were conducted with 10.0 and the other experiments with 10.5 mmol of 2-(4-chlorophenyl)-3-methylbutanoyl chloride. The petroleum ether used in experiment 3 consisted of 97% by weight of alkanes and 3% by weight of benzene and had a boiling range at atmospheric pressure between 62° and 82° C. The ester remained in solution during the reaction in experiments 3 and 4. The reaction mixture obtained in experiment 4 was filtered and the cyclohexane was flashed from the filtrate to give the ester wanted as a colorless oil in quantitative yield. Table IV also presents the yields of the desired ester. Comparison of the yields shows that alkanes and cycloalkanes are the best solvents.
Reaction SMILES: [C:1]1([C:14](Cl)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=O)=[CH:3][CH:2]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=C.C(N(CC[CH2:35][CH3:36])CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:22]([O:21][C:17]([CH:18]=[CH:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([CH:14]=[CH:18][C:17]([O:21][CH2:35][CH3:36])=[O:20])=[CH:2][CH:3]=1)=[O:20])[CH3:23]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)c2ccccc12
Reactant: CCCCN(CCCC)CCCC
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc(C=CC(=O)OCC)c2ccccc12

Procedure:
0.0561 g (0.25 millimol) of palladium acetate, 3.16 g (12.5 millimols) of naphthalene-1,4-dicarboxylic acid dichloride, 3.12 g (31.25 millimols) of ethyl acrylate and 4.63 g (25 millimols) of tri-n-butylamine in 150 ml of p-xylene are stirred for 2 hours at 120° C. The crude product is chromatographed on silica gel in methylene chloride, and then recrystallised from cyclohexane. 2.31 g (57% of theory) of pale yellow crystals, of melting point 90°-91° C., are obtained. Analysis for C20H20O4 : calculated C 74.06%, H 6.22%, O 19.73%; found C 74.04%, H 6.17%, O 19.72%.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:19][CH:18]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)CCN(C)C1
Yield: 1.8 %

Procedure:
5-(4-Chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (500 mg, 2.5 mmol), 4-chlorostyrene (3.18 mL, 25 mmol) and NaH (300 mg, 7.5 mmol) in DMF (10 mL) at 180° C. overnight (16 h) to obtain 15 mg of 5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole after purification. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.30-7.08 (m, 5H), 6.85-6.78 (d, 2H), 4.70-4.60 (d, 1H), 4.40-4.20 (m, 1H), 4.20-4.0 (m, 2H), 3.65-3.50 (m, 1H), 3.10-3.00 (m, 3H), 2.85 (s, 3H), 2.80 (m, 1H), 2.45 (s, 3H), 2.2 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][CH:16]([CH3:18])[CH3:17])[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>CO>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([CH:16]([CH3:18])[CH3:17])[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NC(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1C(=O)CNc2ncc(Br)nc21
Temperature: 90 °C
Yield: 58.8 %

Procedure:
A mixture of ethyl 2-(5-bromo-3-(isopropylamino)pyrazin-2-ylamino)acetate (780 mg, 2.26 mmol), methanol (5 mL) and TFA (10 mL) in a sealable vessel was purged with nitrogen, sealed, stirred vigorously and heated at 90° C. with an oil bath for 16 h. The resulting mixture was diluted with methanol and the solvent was removed under reduced pressure. Methanol (10 mL) was added and the solvent was removed under reduced pressure again. Methanol (10 mL) and sodium bicarbonate were added. The resulting mixture was stirred at room temperature until pH=6 (in water), the solvent was removed under reduced pressure. Water (20 mL) was added. The mixture was extracted with methylene chloride (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, concentrated to give the crude product and purified on silica column chromatography (10-20% ethyl acetate in petroleum ether) to give the title compound (360 mg, 39.4% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[N:2]1.ClC1C=CC([CH2:11][NH:12][C:13](C(C(OCC)=O)C(OCC)=O)=O)=CC=1.ClC1C=CC(C[NH2:34])=CC=1.C(C(OCC)=O)(C(OCC)=O)C(OCC)=O>>[N:3]1[C:4]2[CH:13]=[N:12][CH:11]=[N:34][C:5]=2[S:1][N:2]=1
Reactant: c1csnn1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Reactant: NCc1ccc(Cl)cc1
Agent: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: c1ncc2nnsc2n1

Procedure:
5-Hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamides. As described in Chart BL, (4-morpholinyl)acetic acid trifluoroacetic acid salt BL.1 (J. Med. Chem. 1994, 37, 4538-4554) is cyclized to the thiadiazole BL.2 with aminoguanidine in polyphosphoric acid. Condensation of BL.2 with diethyl ethoxymethylenemalonate followed by thermal cyclization affords thiadiazolopyrimidine BL.3. The resulting ester BL.3 is then saponified to afford the corresponding acid BL.4 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BL.5. A specific example of heterocycle W19.2 in which R8=OH is also prepared as described in Chart BL. Thiadiazole BL.2 is heated in xylenes with diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (prepared by the reaction of 4-chlorobenzylamine with triethyl methanetricarboxylate) to afford thiadiazolopyrimidine BL.6.