Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si](CC)(CC)CC)[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][O:11]2)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(Cl)c(NS(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H]2CO2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
(R)—N-(2-Chloro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (2.2308 g) was dissolved in dehydrated THF (40 mL), and added with 1 mol/L-TBAF-THF solution (10 mL; manufactured by Sigma-Aldrich Co.), followed by replacement with nitrogen and stirring at room temperature for 1 hour. The reaction solution was added to brine, and extraction was carried out once with ethyl acetate. The organic layer was washed once with water and dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=71:29→50:50) to obtain the title compound (0.564 g).
Reaction SMILES: ClC([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:12])=[CH:7][CH:6]=1)=O.CN(C)C=O.CO>C(#N)C>[Cl:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CO
Product: Oc1ccc(CCl)cc1

Procedure:
Equimolar quantities of p-chloromethylphenyl chloroformate and dimethyl formamide were reacted at room temperature for one hour in acetonitrile (590 parts acetonitrile for every mole of dimethyl formamide or p-chloromethylphenyl chloroformate). Equimolar quantities of methanol were then added to the immonium salt mixture, and the solution was then stirred for about one half hour (with cooling) at 25°-30° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=S)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:12].[Na+].OO.[OH-]>O>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]c(=S)sc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 29 (770 mg, 4.2 mmol) in water (30 mL) was added 1N NaOH (4.2 mL) and 30% H2O2 (1.0 mL) and the reaction was stirred for 1 h at room temperature. Additional peroxide (2.0 mL) and hydroxide (5.0 mL) were added and the mixture was stirred for 1 h at 70° C. The reaction mixture was filtered and the filtrate was neutralized with glacial acetic acid. The resulting precipitate was filtered off while still hot, washed with cold water and dried to yield 0.52 g (74%): mp >370 ° C.: UV λmax (pH 1) 267 nm (ε), 289 (): UV λmax (pH 7, 11) 285 nm (ε): 1H NMR (DMSO-d6) δ7.18 (b, 2H, NH2, exchanges with D2O), 8.12 (s, 1 H, C5H), 12.30 (b, 1H, N3H, exchanges with D2O). Anal. Calcd. for C5H4N4OS: C, 35.71: H, 2.40: N, 33.31: S, 19.07. Found: C, 35.50: H, 2.36: N, 33.13: S, 18.79.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:23](CCC2OCCO2)[C:24]#[N:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].BrCCC1OCCO1.C[O:42][C:43]1[CH:44]=[C:45]([CH2:51]C#N)[CH:46]=[CH:47][C:48]=1[O:49]C.IC(C)C.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:24]([C:23]1([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)[O:49][CH:48]([CH2:47][CH2:46][CH:45]([CH3:51])[CH3:44])[CH2:43][O:42]1)#[N:25]
Reactant: COc1ccc(C(C#N)CCC2OCCO2)cc1OC
Reactant: COc1ccc(CC#N)cc1OC
Agent: BrCCC1OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COc1ccc(C2(C#N)OCC(CCC(C)C)O2)cc1OC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A solution of butyllithium (1.6 M solution in hexanes, 7.0 mL, 11.2 mmol) was added via syringe to a solution of diisopropylamine (1.5 mL, 10.61 mmol) in anhydrous THF (25 mL) at −78° C. And then a solution of 2-(3,4-dimethoxyphenyl)-4-(1,3)-dioxolan-2-yl-butyronitrile (18) (709 mg, 2.56 mmol) (previously prepared by reacting 2-(2-bromoethyl)-1,3-dioxolane with 2-(3,4-dimethoxyphenyl)-acetonitrile (14) in a solution diisopropylamine to which butyllithium was added) in THF (10 mL) was added via syringe. The mixture was stirred at −78° C. for five minutes and then 2-iodopropane (0.4 mL, 3.96 mmol) was added. The mixture was stirred at −78° C. for five hours and then at room temperature for 17.5 hours., Saturated NH4Cl solution (10 mL) was added to quench the reaction. Ethyl ether (60 mL) was added and the etheral solution was isolated. The aqueous solution was extracted with ether (2×20 mL). After washing with brine, drying with sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on SiO2 using EtOAc/hexanes (0-30%) to afford the product (19) (397 mg) in 49% yield. 1H-NMR (CDCl3): δ 6.86-6.82 (m, 3 H), 4.80 (t, J=4.2-4.8 Hz, 1 H), 3.95-3.77 (m, 4 H), 3.878 (s, 3 H), 3.867 (s, 3 H), 2.24 (dt, J=3.9-4.2 Hz, J=12.9-13.2 Hz, 1 H), 2.11-2.02 (m, 1 H), 1.91 (dt, J=3.9 Hz, J=12.6 Hz, 1 H), 1.72 (tt, J=3.9-4.2 Hz, J=12.6-13.2 Hz, 1 H), 1.37-1.24 (m, 1 H), 1.16 (d, J=6.6 Hz, 3 H), 0.80 (d, J=6.9 Hz, 3 H). LC-MS: 342.083 (MNa+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[C:8]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[C:17](=O)[CH2:16]3)[CH2:13][CH2:12]1)=CC.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:8][C@H:11]1[CH2:12][CH2:13][C@H:14]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:28]12[CH3:29])[C@:23]1([CH3:24])[C:18](=[CH:19][CH:20]([OH:30])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
Refer to FIG. 189. LAH (21.3 mg, 0.561 mmol) was added to a solution of 17β-methylandrost-4-en-3-one (7, 143.2 mg, 0.4999 mmol) (J. B. Jones and K. D. Gordon, Can. Chem. 1972, 50, 2712-2718) in 2.8 ml of anh. ether. After stirring the suspension for 30 min. Glauber's salt (0.76 g) was added and the mixture stirred a further ½ h. Ether (10 ml) was added and the suspension was filtered through diatomaceous earth. The residue was washed with three 10 ml portions of ether and the combined filtrates were concentrated under reduced pressure. The crude product was separated by preparative TLC (silica gel GF, 1000μ, 5% ethyl acetate/methylene chloride as eluent) into a more polar component (Rf 0.30, 77.9 mg, 0.270 mmol, 54%) and a less polar component (Rf 10 0.43, 10.3 mg, 0.0357 mmol, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=2[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(COc2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
4-Chlorophenol (64.0 mg; 0.5 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile (120.0 mg; 0.5 mmol) [prepared by the method of Ashton and Hynes, J. Med. Chem. 16, 1233 (1973)] in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 140 milligrams of 2-(4-chlorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[CH3:14][O:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[N:22]2)=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.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]>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:2]3[N:3]=[C:4]([O:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[S:5][CH:6]=3)[CH:23]=[N:22]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Reactant: Brc1csc(Oc2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3csc(Oc4ccccn4)n3)cn2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
According to Scheme 3, Step 3: A mixture of 2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.87 mmol, 587 mg), PdCl2(dppf) (0.16 mmol, 127 mg) and N-ethyl-N-isopropylpropan-2-amine (3.11 mmol, 0.53 mL) in dioxane/water (1:1, 10 mL) was stirred at 150° C. for 1 hour under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield 2-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yloxy)pyridine (0.23 mmol, 83 mg, 9%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1F
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetic acid (I55) (1.11 g, 4.12 mmol) in THF (50 ml), were added N,N′-methanediylidenedicyclohexanamine (1.02 g, 4.95 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.67 g, 4.95 mmol), and (R)-quinuclidin-3-ol (0.63 g, 4.95 mmol). The reaction was stirred at RT for hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetate (1.56 g; quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[NH2:11].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:21]Br>O>[Br:21][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([NH2:11])[N:6]=[CH:5][N:4]=2
Reactant: Cn1cnc2c(N)ncnc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(Br)nc2c(N)ncnc21
Reaction time: 2 h

Procedure:
Fifteen grams (0.1 mol) of 9-methyladenine of Example 1 was dissolved in 1.5 liters of buffer prepared from 30.8 g of sodium acetate, 1.4 liters of water and sufficient acetic acid to provide a pH of 4.0. To this solution was added dropwise 25 ml of bromine in 2 liters of water over a period of two hours. The reaction was stirred a further two hours and the resulting solid filtered off and rinsed with the water. The solid was air dried and warmed to about 50° in about 80 ml of methanol, stripped to a hazy suspension and filtered. The precipitate after rinsing with water and drying at 40° under vacuum overnight weighed 15.6 g. The filtrate was stripped of methanol and a further 1.6 g was collected. The combined solids were triturated in about 100 ml of acetone for three hours and then allowed to sit overnight. The resulting precipitate was filtered and washed with acetone to yield 13.3 g after drying at 40° on a vacuum pump overnight.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N>>[OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH:4][C:25]1[CH:24]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:26]=1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethylaniline [Aldrich, product #A41801] as the starting materials. LCMS for C13H16F3N6O4S (M+H)+: m/z=409.1. 1H NMR (500 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.08 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.28 (t, J=5.4 Hz, 1H), 3.36 (q, J=5.8 Hz, 2H), 3.17 (q, J=5.8 Hz, 2H), 2.91 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[O:27]C)[CH3:2].Cl.N1C=CC=CC=1.S(=O)(=O)(O)O.S(Cl)(Cl)=O>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:27])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1OC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 1.07 g (2.69 mmol) of 5-[[2-(2-ethoxy-2-oxoethyl)phenyl]carbonyl]-2-methoxybenzenepropanoic acid ethyl ester and 3.63 g (31.41 mmol) of pyridine hydrochloride was heated at 220°-260° C. for 40 min and then cooled to room temperature. Aqueous 3N sulfuric acid (40 mL) was added, and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was dissolved in 150 mL of ethanol. To this solution was added 3 mL of thionyl chloride and the resulting solution was heated at reflux for 16 hr. The solvent was removed in vacuo and the crude product was purified by flash chromatography on 120 g of silica gel, eluting with 3:1 hexane-ethyl acetate. This afforded 0.469 g (45.4%) of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH2:12][CH:7]12.[Cl-].BrC1C=CC=C2C=1CCN(C(=O)C[NH3+])C2CC(O)=O.C(N(CC)CC)C.Cl>C(Cl)Cl.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12
Reactant: O=C1CC2c3cccc(Br)c3CCN2C(=O)CN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-bromo-1,3,4,7,8,12b-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione. To a stirred solution of 2-(5-bromo-1-(carboxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethanaminium chloride (88 g, 242 mmol) and triethylamine (169 mL, 1210 mmol) in DCM (960 mL), T3P (212 mL, 363 mmol, 50% m/m in AcOEt) was added slowly (exotherm) and the suspension was stirred at rt for 1 h. The solvent was reduced to a small amount under reduced pressure and the thick suspension was treated with 2N aqueous HCl (500 mL). The white suspension was stirred at RT for 15 min and the solid was filtered off. The solid was again treated with 2N aqueous HCl (300 mL), stirred for 10 min and filtered of. The slightly yellow solid was washed with water (1×) and with diethyl ether (2×). The resulting solid was dried at 50° C. under high vacuo overnight to yield the title compound as beige solid (71 g). UPLC-MS: MS 309.1/311.1 (M+H+); UPLC rt 0.72 min.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1.CCOC(C)=O>CN(C=O)C>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1C(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(SC)ccc1C(C)=O
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
Sodium thiomethoxide (3.35 g, 47.8 mmol) was dissolved in dry DMF (35 ml) under a blanket of nitrogen. The solution was cooled to −15° C. and 1-(4-fluoro-2-methoxyphenyl)ethanone (6.7 g, 39.8 mmol) was added in portions. After 10 min at −15° C. the reaction mixture was brought to 0° C. for 1.5 h. EtOAc was added and the organic phase was washed three times with aqueous HCl (10%), dried (Na2SO4) and evaporated under reduced pressure to dryness. Purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (6.3 g, 81%). MS m/z (rel. intensity, 70 eV) 196 (M+, 37), 182 (11), 181 (bp), 166 (7), 138 (10).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:3]=1.[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.CO>[NH:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:33]3[CH2:34][CH2:35][CH2:36][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]3)[CH:3]=2)=[CH:9]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(Cl)ncn3)c3cccnc32)cc1
Reactant: CC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1CCCN(c2cc(-c3c[nH]c4ncccc34)ncn2)CC1
Yield: 71.9 %

Procedure:
A solution of 8 (0.035 g, 0.091 mmol), N-acetyl-homopiperizine (0.025 g, 0.181 mmol), excess potassium carbonate in DMF was heated at 80° C. resulting in a color change after 5 minutes. LC/MS and TLC indicated conversion to tosyl protected product after 15 minutes. 1 ml of 6N NaOH and 1 ml of methanol were added to the reaction resulting in the immediate removal the tosyl group by LC/MS (M+1=337). The reaction was partitioned between EtOAc/H2O and extracted. The crude product was purified by preparative HPLC giving 9 (0.022 g) as a clear oil in 73% yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].CC(C)([O-])C.[Na+].[O:13]=[CH:14][CH2:15][CH2:16][C:17](OCC)=O.N>C(O)CC>[CH2:16]1[CH:17]2[NH:6][C:4]([CH2:3][N:2]2[C:14](=[O:13])[CH2:15]1)=[O:5]
Reactant: CCOC(=O)CCC=O
Reactant: NCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: N
Solvent: CCCO
Product: O=C1CN2C(=O)CCC2N1
Temperature: 65 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A suspension of 90.0 g (0.798 mol) of glycinamide hydrochloride (purity 98%) in 7.2 liter of n-propanol is heated to reflux, and 250 ml of solvent are distilled off. A 15% w/v solution of sodium tert-butoxide in n-propanol (260 ml, 0.35 mol) are added and an apparent pH of 5.5 is measured. Maintaining this apparent pH at 5.5 by automatic addition of a 15% w/v solution of sodium tert-butoxide in n-propanol, ethyl 4-oxobutanoate (purity 97%) (262.3 g, 1.955 mol) is added dropwise during four hours while keeping the reaction mixture at reflux, continuously distilling the solvent at about 400 ml/h and continuously adding n-propanol to the reaction mixture at about 400 ml/h. A total amount of 363 ml (0.476 mol) of sodium tert-butoxide 15% w/w solution in n-propanol is added. The mixture is stirred at reflux for additional 1.5 hours and then cooled to 65° C. A 7.5% w/w solution of ammonia in n-propanol (800 g) is slowly added to the mixture during 6 hours, and heating at 65° C. is continued for additional 18 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The clear solution is concentrated to a small volume (about 0.5 liter) under vacuum and stirred at 0° C. for 2 hours. The white precipitate is collected by suction filtration, washed with 50 ml of n-propanol and dried under vacuum at 60° C. for 12 hours to afford pure dimiracetam (65 g, 58.1%), melting at 154° C. HPLC purity: 99.7%
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32]O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][O:22][C:19]3[CH:18]=[N:17][C:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=4)=[N:21][CH:20]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Product: CCCCCCCCOc1ccc(-c2ncc(OCc3ccc4c(c3)OCO4)cn2)cc1

Procedure:
By Mitsunobu etherification of 2-(4-octyloxyphenyl)pyrimidin-5-ol using benzo[1,3]dioxol-5-ylmethanol analogously to Example 208.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-iodo-5-bromo-1H-pyrrolo[2,3-b]-pyridine (500 mg, 1.55 mmol) in CH2Cl2 (4.1 ml) are added 60% sodium hydride (186 mg, 4.66 mmol) and benzyltriethylammonium chloride (8 mg, 0.03 mmol) under argon at 0° C. After 30 minutes, benzenesulfonyl chloride (240 μl, 1.86 mmol) is added at 0° C. and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with water and extracted several times with CH2Cl2. The organic phases are combined, dried on MgSO4 and concentrated under reduced pressure. The residue is precipitated with methanol and the resulting solid filtered to yield the expected product in the form of a pink solid with 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[CH3:18]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:18])[C:6]=2[CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 4.85 g of methyl 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate in 30 ml of dimethylformamide is added 2.7 g of potassium t-butoxide and solution stirred at room temperature for 30 minutes. To the resultant solution is added dropwise a solution of 3.4 g of methyl iodide in 10 ml of dimethylformamide under stirring. After the reaction solution is stirred for 1.5 hours, 200 ml of water is added thereto. The insoluble substance is collected by filtration, washed with water and dried to give 5.1 g of methyl 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, melting at 128°-130° C.