Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13]>>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: N
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Product: CC1(C)CC(N)CC(C)(CN)C1
Reaction time: 0.73 h

Procedure:
In a continuously operated laboratory apparatus comprising a first reactor charged with 100 ml of Al2O3 (4 mm extrudates) and a second reactor charged with 240 g (200 ml) of the Raney catalyst produced as described in example 1, 32 ml/h of isophoronenitrile are hydrogenated by means of 300 ml/h of H2 in the presence of 147 ml/h of NH3 at 250° C. and a pressure of 250 bar. The space velocity over the catalyst is 0.15 kg/l (catalyst)*h, and the residence time is 44 minutes. At a conversion of 99.2%, isophoronediamine is obtained with a selectivity of 89.5%. The cis/trans isomer ratio is 79:21.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH:12][CH2:11]3>>[CH3:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C@H:5]1[OH:23])[C@:18]1([CH3:19])[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH:12][CH2:11]3
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H]1C[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1O

Procedure:
Sodium borohydride is added to the 16β-methly-5-androsten-17-one(produced in F hereinabove) according to the procedure described in Example 8F to form mostly the above-identified final product and a smaller amount of 16β-methly-5-androsten-17α-ol which are separated by HPLC on a silica gel column.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:9])[O:7][CH3:8].Cl[CH2:11][O:12][CH2:13][C:14]#[CH:15].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:11][O:12][CH2:13][C:14]#[CH:15])[C:6](=[O:9])[O:7][CH3:8]
Reactant: C#CCOCCl
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCN(OC)C(=O)OC
Yield: 75.9 %

Procedure:
0.37 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 0.8 g of methyl N-methoxycarbamate and 0.96 g of chloromethylpropargyl ether were added thereto in this order while being cooled with ice. The mixture was heat-refluxed for 1 hour. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 1.0 g of methyl N-methoxy-N-propargyloxymethylcarbamate.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]([C:16]1[S:17][C:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:20]=1)=[O:15])[CH2:9]2>N1C=CC=CC=1.O>[CH:12]12[CH2:13][CH:8]1[CH2:9][N:10]([C:14]([C:16]1[S:17][C:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:5](=[O:7])[CH3:6])(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[N:20]=1)=[O:15])[CH2:11]2
Reactant: NS(=O)(=O)c1ccc(-c2sc(C(=O)N3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-c2sc(C(=O)N3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Acetic anhydride (0.66 g, 0.65 mmol) was added to stirred solution of 44243-azabicyclo[3.1.0]hexane-3-carbonyl)-4-(4-chlorophenyl)thiazol-5-yl)benzenesulfonamide (Compound 73, 0.3 g, 0.65 mmol) in pyridine (5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.07 g, 21.4%). MS: m/z 502 (M+1).
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1>[Br:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
Add borane-THF (1 M in THF, 3.2 mL) complex dropwise to an ice-cooled solution of 2-bromo-4-chlorobenzoic acid (500 mg, 2.1 mmol) in THF (2 mL). Remove the cooling bath and stir overnight. Slowly add water (1 mL) and solid sodium carbonate. Stir 1 h. Filter and wash solids with THF. Chromatograph on silica gel, eluting with 0:100 to 30:70 ethyl acetate:dichloromethane to give 2-bromo-4-chlorobenzyl alcohol as a white solid (378 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford the acid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]1([Mg]Br)[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:15]([CH2:21][CH3:22])[CH2:14]1)[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH2:19]([C:17]1([C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[C:13]([CH2:11][CH3:12])[CH:14]=[C:15]([CH2:21][CH3:22])[CH2:16]1)[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC1=CC(CC)([Mg]Br)CC(CC)=C1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1(CC)C=C(CC)C=C(CC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
On the other hand, to a 3 L volume four-necked flask, diethyl oxalate (295 g) and tetrahydrofuran (anhydrous) (350 ml) were added under a nitrogen atmosphere and cooled on ice-bath. The above mentioned solution of 1,3,5-triethylphenylmagnesium bromide in, tetrahydrofuran was added thereto with keeping the temperature below 10° C. The resulting mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to less than 2 with 20 w/w % of sulfuric acid under ice-cooling. The mixture was extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 495.3 g of ethyl 2-(1,3,5-triethylphenyl)-2-oxoacetate (9-b).
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8]
Reactant: Cn1cc(C(=O)NOC(C)(C)C)c(Nc2ccc(Br)cc2F)c(F)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)NO)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 96 h
Yield: 33 %

Procedure:
4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydroxyamide was prepared from 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxy-amide by TFA mediated deprotection. 4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxy-amide (35 mg, 0.081 mmol) was treated with TFA (0.63 mL). After 4 days stirring, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (10% MeOH in methylene chloride) followed by saturated NaHCO3 solution wash of an ethyl acetate solution of the product gave clean desired product (10 mg, 33%); MS APCI (+) m/z 356, 358 (M-OH, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.84 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H), 3.57 (s, 3H).
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:17][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]2=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2c1c1ccccc1n2Cc1ccccc1
Yield: 41.9 %

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and was then stirred with benzyl bromide (513 mg) at room temperature for 30 min. Purification by FCC eluting with dichloromethan: ethanol (80:1) gave the title compound (347 mg), m.p. 209°-212°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[O:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]([C:32]1[S:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>CN(C=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]>[ClH:7].[C:29]([C:32]1[S:36][C:35]([C:27]2[C:21]3[O:20][C:19]([C:17]([NH:16][C@@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[O:18])=[CH:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)=[CH:34][CH:33]=1)(=[O:31])[CH3:30]
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)s1
Temperature: 70 °C

Procedure:
0.58 ml of 2 M aqueous sodium carbonate solution and 15.9 mg (0.02 mmol) of PdCl2(dppf) are added to a mixture of 150 mg (0.39 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 66.1 mg (0.39 mmol) of 5-acetyl-2-thienylboronic acid in 2 ml of DMF. The reaction mixture is heated at 70° C. for 18 h and then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of a 1:1 mixture of methanol and 1N hydrochloric acid, concentration and drying under high vacuum result in 83.6 mg (49.9% of theory) of the title compound.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].Br[C:6]1[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH2:15])[C:7]=1[C:8]#[N:9]>O>[NH2:15][C:10]1[C:7]([C:8]#[N:9])=[C:6]([O:3][CH2:1][CH3:2])[N:13]=[C:12]([NH2:14])[CH:11]=1
Reactant: CCO
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Na]
Solvent: O
Product: CCOc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 65 %

Procedure:
To a 5 mL sealable heavy walled glass tube suitable for microwave heating containing 5 mL of absolute ethanol was added 150 mg (6.5 mmol) of sodium metal. The mixture was stirred until all of the sodium had reacted, then 1.00 g (4.71 mmol) of 2-bromo-4,6-diaminonicotinonitrile (E. I. du Pont de Nemours and Company U.S. Pat. No. 2,790,806, 1957) was added. The tube was sealed, and the reaction was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and diluted with 15 mL of water. The orange precipitate which formed was washed with water until pH=7, then dried under reduced pressure at 105° C. to provide 0.545 g (65%) of a light orange solid. 1H NMR (300 MHz, d6-DMSO) δ 6.19 (s, 2H), 6.14 (s, 2H), 5.32 (s, 1H), 4.23 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz), MS (ES) m/e=151 (M−Et+H)+, 179 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[CH:7]=[C:6]([C:23]([O:25]CC)=[O:24])[CH:5]=1)[CH3:2].[OH-].[K+]>O.O1CCOCC1>[CH2:1]([O:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:19][CH2:20][CH3:21])[C:9](=[O:22])[C:8]=2[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2c(c1)C(=O)c1cccc(OCC)c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cccc2c1C(=O)c1c(OCC)cc(C(=O)O)cc1C2=O
Reaction time: 0.25 h

Procedure:
4,5-Diethoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid, ethyl ester (2.67 g) and crushed potassium hydroxide (1.22 g) were dissolved by magnetically stirring in water (13 ml) and dioxan (26 ml). Within 15 minutes a mustard coloured solid began to separate.
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[CH:3]=[C:4]4[O:5][CH2:6][CH2:7][CH2:8][N:9]4[N:1]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc2n(n1)CCCO2
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCCO2
Yield: 53.3 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid (0.078 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile and by flash-chromatography, respectively. Yield 53.3%. 1H-NMR (400 MHz; CDCl3): δ 1.19 (d, 3H), 2.26-2.34 (m, 2H), 4.18-4.34 (m, 5H), 4.41 (dd, 1H), 4.52-4.62 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.70-7.75 (m, 21-1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc(NC(C)=O)cc3)n2)cc(OC)c1OC
Yield: 37 %

Procedure:
Using Method EE with 2-chloro-6-(4-acetamidophenyl-oxy)-pyrazine (150 mg, 0.57 mmol) and 3,4,5-trimethoxyaniline (125 mg, 0.68 mmol), and crystallisation (AcOEt), the title compound was obtained (87 mg). Yield: 37%. 1H NMR (250 MHz, DMSO-d6) δ 2.07 (s, 3H, CH3—NH), 3.43 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom2′+6′), 7.13 (d, 2H, Harom 3+5, J=8.9 Hz), 7.60 (d, 2H, Harom 2+6, J=8.9 Hz), 7.73 (s, 1H, HPz 5), 7.93 (s, 1H, HPz 3), 9.51 (s, 1H, NH), 9.98 (s, 1H, NH). m/z: 411.2 [(M+H)+, calcd for C21H22N4O5 410.2].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[S:1]1[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2,2′-bithiophene (10.0 g, 60.24 mmol) in dry THF (150 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 6-bromohexyloxy-tert-butyidimethylsilane (14.75 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. ammonium chloride, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, petroleum/ethyl acetate from 100:0 to 20:1), to afford the product as a pale green oil (15.07 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.08 (m, 1H, Ar—H), 7.03,(m, 1H, Ar—H), 6.92 (m, 2H, Ar—H), 6.61 (d, J=3.6 Hz, 1 H, Ar—H), 3.55 (t, J=6:2 Hz, 2H, OCH2), 3.34 (t, J=6.8 Hz, 2H, ArCH2), 1.25–1.85 (m, 8H, CH2), 0.86 (s, 9H, CH3), 0.01 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm).145.1 (quat.), 138.0 (quat.), 134.8 (quat.), 127.6 (CH), 124.7 (CH), 123.7 (CH), 123.4. (CH), 122.9 (CH), 63.0 (OCH2), 33.8 (CH2), 32.9 (CH2), 32.7 (CH2), 28.0 (CH2), 26.0 (CH3) 25.1 (CH2), 18.4 (quat.), −5.2 (CH3); MS (m/e): 380 (M+, 27%), 323 (63), 179 (100), 75 (37).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[S:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14].Cl>N1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[S:7][C:6](=[O:8])[CH:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:4](=[O:9])[CH2:3]1
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)S1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccncc1
Product: CCCC(=O)C1C(=O)CC(C)(C)SC1=O
Yield: 42.3 %

Procedure:
9.6 g (0.07 mol) of zinc chloride are first added to 5 g (0.035 mol) of 6,6-dimethyltetrahydrothiopyran-2,4-dione in 100 ml of pyridine, after which 3.7 g (0.03 mol) of butyryl chloride are added dropwise. When the addition is complete, the mixture is heated to the reflux temperature for 4 hours, and the cooled reaction mixture is poured into 200 ml of semi-concentrated hydrochloric acid, the mixture is extracted several times with dichloromethane, the combined organic phases are dried over magnesium sulphate, and the solvent is removed in vacuo. 2.9 g (36.6% of theory) of 6,6-dimethyl-3-butyryltetrahydrothiopyran-2,4-dione are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O>>[CH2:13]1[N:1]2[C:16](=[N:11][S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=32)[CH2:15][CH2:14]1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1S(N)(=O)=O
Product: O=S1(=O)N=C2CCCN2c2ccccc21

Procedure:
2-Aminobenzene-sulfonamide was transformed by Method E (using 4-chlorobutanoyl chloride).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:38][CH:37]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(Cl)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)cc1

Procedure:
Compound 45 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [357 (M+H)].
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](NCC(OCC1C=CC=CC=1)=O)=[O:19].[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41].C(N1CCOCC1)C.Cl>CN(C)C=O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:19]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)NCC(=O)OCc2ccccc2)c2ccccc2)=C(C)C1=O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)N2CCC[C@H]2C(=O)O)c2ccccc2)=C(C)C1=O
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To a mixture of benzyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoylglycinate (0.95, 2.0 mmoles) and L-proline (0.24 g, 2.1 mmoles) was added a solution of N-ethylmorpholine (0.48 g, 4.2 mmoles), in dimethylformamide (10 ml) at room temperature. After 15 hours, 1N hydrochloric acid (5 ml) was added to the reaction mixture. The product was extracted with ethylacetate. The extract was worked up in the usual manner. The crude product was chromatographed on a reversed phase ODS column (YMC-Gel ODS, 60/200 mesh, Yamamura Chemical Co. Kyoto) with methanol-H2O (9:1) as eluant to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoyl-L-proline (0.64 g, 71%) as an oil.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl>C(Cl)Cl>[CH2:18]([O:17][C:15]([N:13]1[CH2:12][CH2:11][S:10][C:9]1=[S:8])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: SC1=NCCS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCSC1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12.9 ml of triethylamine cooled to 0° to 5° C. were added to 10 g of mercapto-thiazoline in solution in 200 ml of methylene chloride, then 12 ml of benzyl chloroformate in solution in 60 ml of methylene chloride were added dropwise. After stirring for 3 hours at ambient temperature, the mixture was poured into an iced solution of N hydrochloric acid and the aqueous phase was extracted with methylene chloride. The organic phase was dried and concentrated to dryness and the residue was chromatographed on silica (eluant: hexane-ethyl acetate 7-3) to obtain 17.9 g of the expected product melting at 72° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].O>S(=O)(=O)(O)O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., an the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2×30 ml) and water (30 ml), dried (Na2SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetronitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214°-216° C. Found: C,57.36; H,5.21; N,19.49. C17H19N5O4 requires C,57.13; H,5.36; N,19.60%.