Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][NH:5][C:4]2[N:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:5]2[C:4]3[N:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2](=[O:1])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6]2)=[CH:20][CH:19]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)c1n[nH]c2ncccc2c1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (1.00 g, 4.56 mmol) and 2-chloro-5-(chloromethyl)pyridine [(Example 5, Step 1), 500 mg, 2.28 mmol] and 4-iodobenzylbromide (745 mg, 2.51 mmol, 1.1 equiv) were dissolved in degassed N,N-dimethylformamide (5 mL) and cooled to 0° C. The mixture was treated with sodium hydride (109 mg, 2.74 mmol, 1.2 equiv) portionwise over 5 minutes. After stirring for 2 hours at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 2 hours. The mixture was treated with sodium bicarbonate (10 mL, aqueous saturated), poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:20])[CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH:9]1[CH2:10][N:11]([C:13](=[O:20])[CH2:14][C:15]([OH:17])=[O:16])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CC(COc2ccc(Cl)cc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cl)ccc1OCC1CN(C(=O)CC(=O)O)C1
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred solution of ethyl 3-{3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoate (285 mg, 0.78 mmol) obtained in Example 208 in THF (5.0 ml) was added lithium hydroxide (1.0M aqueous solution, 5.0 mL, 5.0 mmol) at room temperature. After 3 hr, the reaction mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (203 mg, 77%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][N:22]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:20])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 53 mg of the title compound (57%) as a orange powder in 93% purity by HPLC (Rt: 4.11, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([CH2:57][C:58]1[O:59][CH:60]=[CH:61][CH:62]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: O=C=NCc1ccco1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccco1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 40% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z=574.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[N:18]1([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccc(CN2CCCCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
DIEA (433 μl, 2.49 mmol) was added into a suspension of 3-bromobenzenamine (90.34 μl, 0.829 mmol), 4-(piperidin-1-ylmethyl)benzoic acid (200 mg, 0.912 mmol), BOP (477 mg, 1.08 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was loaded onto a 5 g silica loading cartridge. After solvent in the cartridge was dried out under vacuum, the cartridge was put on the ICSO system for purification (yield: 80%). MS (ESI+) m/z 373.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
N-(4-(methylthio)phenyl)methanesulfonamide (200 mg, 0.920 mmol) was dissolved in DMF (3 ml). K2CO3 (254 mg, 1.841 mmol) and tert-butyl 2-bromoacetate (359 mg, 1.841 mmol) were added, and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water and filtered. The precipitate was dissolved in EtOAc and extracted with water and HCl 1M, dried over Na2SO4 and concentrated under vacuum to give tert-butyl 2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetate (220 mg, 72.1% yield).
Reaction SMILES: CC1(C)S[C@@H]2[C@H](N[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])C(=O)N2[C@H]1C(O)=O.C(O)([OH:28])CCC>>[C:14]1([CH2:13][C:11]([OH:12])=[O:28])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC(O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: O=C(O)Cc1ccccc1

Procedure:
A solution of 40 mM of 6 APA and 200 mM of phenylacetic acid in 50% butanediol/50% acetate 50 mM is prepared at a pH of 6.5. The column is thermostatized at 4° C. The rest of the conditions are as in example 1. In these conditions, the degree of conversion of 6 APA to penicillin G is higher than 85%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][C:23](O)=[O:24])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:26][C:27]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:23](=[O:24])[CH2:22][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][C:11]1=2
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)Cn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetic acid (3.38 mmol) was dissolved in THF (20 mL) and 2,3-dimethylaniline (0.43 mL, 0.43 g, 3.6 mmol, 1.05 equiv.), dimethylaminopyridine (0.415 g, 3.40 mmol, 1.01 equiv.), and diisopropylcarbodiimide (0.60 mL, 0.48 g, 3.8 mmol, 1.13 equiv.) were added. The reaction mixture was stirred at rt under N2 for 18 h. The reaction mixture was taken up in EtOAc (100 mL) and this solution was washed with 10% aqueous citric acid (2×50 mL), 5% aqueous NaHCO3 (2×50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (1.7223 g) was chromatographed (SiO2 187 g, eluted with 10:1 toluene:acetone followed by 9:1 toluene:acetone) to give tert-butyl 6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.1066 g) in 67% yield. 1H NMR (300 MHz, CD3OD) δ 1.50, 2.01-2.03, 2.27, 2.29-3.12, 3.66-3.75, 3.75-3.83, 5.03, 7.04-7.19, 7.37, 7.49; MS (ESI+) for C27H33N3O3 m/z 448.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COCCOc1nc(N)c2ncn(Cc3cccc(C(=O)OC)c3)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(C(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
A solution of Compound (4) (4.09 g, 11.45 mmol) and sodium acetate (14.26 g, 171.84 mmol) in acetic acid (50 mL) was cooled to 0° C. in an ice bath. Bromine (23.8 g, 148.93 mmol) was added dropwise by syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight (16 hr), and subsequently quenched with saturated sodium sulfite solution. The quenched reaction mixture was extracted with dichloromethane (3×50 mL), dried over sodium sulfate and solvent evaporated to give Compound (5) as a yellow solid (3.35 g, 67% yield). 1H NMR (300 MHz, CDCl3) δ 3.44 (s, 3H), 3.77 (t, J=5.1, 9.9 Hz, 2H), 3.92 (s, 3H), 4.52 (t, J=4.8, 9.9 Hz, 2H), 5.35 (s, 2H), 7.41 (t, J=7.5, 13.5, Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 8.09 (s, 1H). LCMS: m/z for C17H18BrN5O4++H observed 437.0 and 438.0 at 3.62 minutes of a 6 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([NH:29][C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cc2cc(N)ccc2o1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2o1

Procedure:
Carboxylic acid (56) (60 mg, 0.32 mmol) was coupled to 5-amino-benzofuran-2-carboxylic acid ethyl ester (65 mg, 0.32 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.S(Cl)(Cl)=O.[CH3:30]O>>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH3:30])=[O:24])(=[O:21])=[O:20]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To a slurry of bumetanide (1.2 g, 3.29 mmol) in methanol (12 mL) under nitrogen, was added a mixture of thionyl chloride (70 uL) in methanol (6 mL) over 5 minutes. After stirring for 5 minutes the reaction mixture became soluble. The reaction was stirred for an additional 30 minutes, at which time the reaction was complete as determined by thin layer chromatography (TLC). The methanol was removed under reduced pressure and the residue was brought up in ethyl acetate and washed with saturated sodium bicarbonate, water and brine. The ethyl acetate was dried over anhydrous magnesium sulfate and concentrated to yield 1.1 g (89%) of methyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])[C:4]=2[CH:3]=[CH:2]1.[N+:25]([O-])([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][CH2:11][O:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])c2sccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
286 g (0.853 mol) of 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole were suspended in 6.3 l of glacial acetic acid. Temperature was raised to 60° C. The resulting clear solution was cooled to 25° C. 132 ml (3.18 mol) of 100% nitric acid were added within 3 minutes. The reaction mixture was cooled below 30° C. After crystallization the suspension was stirred at 18 to 20° C. for 1 hour. The precipitate was filtered with suction and washed with 2×600 ml of tert-butyl methyl ether. The residue was suspended in 4 l of acetic ester for 15 minutes. 200 g (1.9 mol) of sodium carbonate in 3 l water were added. The resulting suspension was stirred for 1 hour. Acetic ester was distilled off followed by addition of 2 l of water. The suspension was stirred for 30 minutes. The precipitate was filtered with suction, washed with water and dried (50° C., 24 hours).
Reaction SMILES: C(N(CC)CC)C.C(O[CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])(=O)C.[CH2:19]([SH:21])[CH3:20].Cl>C(#N)C>[CH2:19]([S:21][CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])[CH3:20]
Reactant: CCS
Reactant: CCC(C[N+](=O)[O-])OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSC(CC)C[N+](=O)[O-]
Reaction time: 1 h
Yield: 86 %

Procedure:
2-Ethylthio-1-nitrobutane was prepared by dropwise addition of a solution of triethylamine (16.77 g., 0.166 mol) and acetonitrile (50 ml.) to a stirred solution of 2-acetoxy-1-nitrobutane (26.50 g., 0.164 mol) and ethanethiol (11.20 g., 0.164 mol) over 30 minutes at 0°-5° C. Upon complete addition, the resulting solution was stirred for 1 hour at 0°-5° C., and then was poured into dilute aqueous hydrochloric acid solution (500 ml.). The organics were extracted into methylene chloride (3×150 ml.) and the combined portions were washed with deionized water (2×200 ml.), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled (1.5 Torr., 72°-75° C., internal) yielding a clear oil, 23.03 g., 86% yield. 1H-NMR (CDC13): δ 1.1, t, 3H, --CH3 ; 1.29, t, 3H, SCH2CH3 ; 2.5-2.85, m, 2H, --CH2 --; 2.6, q, 2H, SCH2 --; 3.28, m, 1H, CH; 4.5, d, 2H, --CH2NO2.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]([CH2:18][C:19]3[N:24]=[CH:23][N:22]4[CH:25]=[C:26]([C:28]([NH2:30])=O)[N:27]=[C:21]4[C:20]=3[CH2:31][CH2:32][CH3:33])[CH:15]=[CH:16][N:17]=2)[CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[F:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]([CH2:18][C:19]3[N:24]=[CH:23][N:22]4[CH:25]=[C:26]([C:28]#[N:30])[N:27]=[C:21]4[C:20]=3[CH2:31][CH2:32][CH3:33])[CH:15]=[CH:16][N:17]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(N)=O)nc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C#N)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
POCl3 (0.5 ml) is added to a solution of 128 (0.75 mmol) in pyridine (3 ml) and the mixture is stirred at room temperature overnight. The solvent is evaporated and the residue is purified by PTLC (5% MeOH in CH2Cl2) to afford the product (127); LC-MS, M+1 362.1; 1H-NMR (CDCl3) δ: 8.77 (s, 1H), 8.11 (dd, 1H), 8.03 (s, 1H), 7.82 (q, 1H), 7.19 (s, 1H), 7.18 (s, 1H), 6.82 (dd, 1H), 6.03 (s, 2H), 3.11–3.17 (m, 2H), 1.67–1.75 (m, 2H), 1.01 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][NH2:26]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][C:19]2[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])[N:3]=1
Reactant: NNc1c(Cl)cccc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NNc2c(Cl)cccc2Cl)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dichlorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:4][CH2:3][CH2:2][Br:1])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: BrCCCOc1ccc(Br)cc1

Procedure:
The title compound was prepared and worked up by the method of Example 6 using 4-bromophenol in place of 3,4-dichlorophenol. After chromatography the title compound (3.45 g) was found to be homogeneous by thin layer chromatography (10% by volume of methylene chloride/hexane on silica gel plates).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:14][CH:13]=1>O1CCOCC1>[CH:1]([NH:4][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[N:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:14][CH:13]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of isopropylamine (95 μL, 1.11 mmol) in dioxane (5.5 mL) was added dropwise trimethylaluminium (2 M in heptane, 600 μL, 1.11 mmol). The resulting solution was stirred at room temperature for 1 h, then a solution of 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester (90 mg, 0.28 mmol) in dioxane (2.8 mL) was added and the reaction mixture was stirred at 90° C. for 5 h. After cooling to room temperature the mixture was poured into a Na—K-tartrate solution extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (83 mg, 85%) as a white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1.[CH3:11][SH:12].O1CCCC1.[Na]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][F:10])[CH:5]=[C:6]([S:12][CH3:11])[N:7]=1
Reactant: Nc1nc(F)cc(CF)n1
Reactant: CS
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1cc(CF)nc(N)n1
Reaction time: 1 h

Procedure:
A mixture of 1.0 part of 2-amino-4-fluoro-6-fluoromethylpyrimidine, 3.0 parts of methanethiol and 50 parts of dry tetrahydrofuran was stirred at 5° C. whilst a solution of 0.16 parts of sodium in 20 parts of dry methanol was added dropwise. The temperature was kept below 10° C. with ice-bath cooling. When the addition was complete, stirring was continued for 1 hour. The resulting solution was evaporated and the residue was diluted with water and extracted three times with 50 parts of ether. The ethereal solutions were combined and dried (MgSO4). The solvent was evaporated and the crude product was purified by recrystallisation from carbon tetrachloride to give 2-amino-4-fluoromethyl-6-methylthiopyrimidine m.p. 95°-97° C.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:15])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1>>[CH3:15][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[CH:2]([CH2:3][CH3:4])[C:1]([OH:6])=[O:5]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C1CCCO1
Product: CCC(C(=O)O)c1c(C)cc(C)cc1C
Yield: 33.5 %

Procedure:
In the same 100 ml autoclave as in Example 1, 1.5 g of tungstosilicic acid, 40 ml of mesitylene and 2.55 ml of γ-butyrolactone were charged and reacted at 180° C. for 6 hours, and then analysis was conducted. As a result, the conversion ratio of γ-butyrolactone was 85.1% and 2,4,6-trimethylphenylbutyric acid (yield based on γ-butyrolactone: 33.5%) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccsc3)CC12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(3-thienyl)acetic acid (0.99 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.24 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C., then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-thienyl)acetyl]-4-perhydroisoindolone (2.2 g) melting at 224° C. is obtained.