Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[C:13]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1>[C:13]([C:17]1[CH:18]=[C:19]([NH:20][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 96 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-tert-butylaniline (206 mg, 1.381 mmol). The mixture was heated in microwave for 10 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 78 mg 5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (96% yield). LCMS (M+1=295)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([Br:21])[C:13]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([Br:21])[C:13]=1[CH2:22][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNCc2c(Br)cc([N+](=O)[O-])cc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-methoxybenzylamine (2.15 g, 15.7 mmol) was added to a solution of 1,3-dibromo-2-(bromomethyl)-5-nitrobenzene (4.91 g, 13.1 mmol) in DMF (100 mL) under nitrogen at rt. K2CO3 (1.99 g, 14.4 mmol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 500 mL of water, and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography on Biotage 40M columns, eluting with 90:10 hexanes-ethyl acetate to provide N-(2,6-dibromo-4-nitrobenzyl)-N-(4-methoxybenzyl)amine as a red viscous liquid. 1H NMR (500 MHz, CDCl3): δ 3.81 (d, J=3.6 Hz, 4H); 4.20 (s, 3H); 6.88 (d, J=8.4 Hz, 2H); 7.27 (d, J=5.9 Hz, 2H); 8.40 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cn2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
[3-(5-Bromo-pyridin-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (38.8 g, 150.5 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (29.2 ml, 210.7 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (12.3 ml, 180.6 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (30.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[O:10][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:9][C:4]=2[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(Br)Br
Reactant: Oc1ccc(Cl)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(Cl)c(Cl)c2O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A mixture of 11.0 g of 3,4-dichloro-1,2-benzenediol, 15.38 g of potassium carbonate, 27 g of ethyl dibromoacetate and 100 ml of dimethylformamide is stirred at 100° C. under argon gas atmosphere for 4 hours. The reaction mixture is evaporated to remove solvent and ethyl acetate and water is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 10.75 g of ethyl 4,5-dichloro-1,3-benzodioxole-2carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12](O)=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][NH2:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1)[CH2:25][NH:26][C:12]([C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3=[O:1])[CH2:10]1)[CH2:6]2)=[O:13]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CNC(=O)C23CC4CC(C2)C(=O)C(C4)C3)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
4-oxoadamantane-1-carboxylic acid (200 mg, 1.03 mol), (3,5-dimethoxyphenyl)methanamine (172 mg, 1.03 mmol), EDCI (410 mg, 2.06 mmol), and HOBt (280 mg, 2.06 mmol) were dissolved in dry CH2Cl2. DIEA (1.3 g, 10 mmol) was added under nitrogen at 0° C. and the mixture was stirred overnight at rt. The mixture was washed with water and brine. The organic layer was dried and concentrated to give crude product which was purified by preparative TLC to give N-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide (231 mg, 65%). 1H NMR: (400 MHz, CDCl3): δ=1.62 (s, 4H) 1.95-2.25 (m, 13H), 2.59 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.35 (d, 2H), 6.05 (s, 1H), 6.44 (m, 2H), 7.15 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:4][CH:3]=1.[OH:44]OS([O-])=O.[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[O:44])=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(SCc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S(=O)Cc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.108 mmol, example 129, step 2) in THF (4 mL) and water (2 mL) was added Oxone (73 mg, 0.119 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with aqueous sodium thiosulfate, partitioned between DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (1:0 to 1:1) to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione (60 mg, 97.6%) as yellow oil. LCMS retention time 1.499 min; LCMS MH+-THP 571.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42](=[O:63])[NH:43][C:44]1([CH2:47][N:48]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@@H:49]([CH2:54]O)[CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:46][CH2:45]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[CH2:50]([C@H:49]1[N:48]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[CH2:47][C:44]2([CH2:45][CH2:46]2)[N:43]([C:42]([O:41][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:63])[CH2:54]1)[CH:51]([CH3:52])[CH3:53]
Reactant: CC(C)C[C@H](CO)N(CC1(NC(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1CN(C(=O)OCc2ccccc2)C2(CC2)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
Triphenylphosphine (1.57 g, 5.99 mmol) and diisopropyl azodicarboxylate (0.93 ml, 4.49 mmol) were added to a toluene (100 ml) solution of the compound (1.26 g, 3.00 mmol) obtained in Step 3 above under ice cooling and the resulting mixture was gradually returned to room temperature while being stirred for 18 hours. Further triphenylphosphine (1.57 g, 5.99 mmol) and diisopropyl azodicarboxylate (0.93 ml, 4.49 mmol) were added and the resulting mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (0.57 g, 47%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[N:14]=[C:13]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Brc1cccc(COC2CCCCO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(COC2CCCCO2)nc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 7.4 %

Procedure:
Imidazole (500 mg, 74 mmol) was added to a stirred mixture of sodium hydride (300 mg of a 60% dispersion in oil, 75 mmol) and dimethylformamide (20 ml), at room temperature under nitrogen. After 0.75 h, 6-bromo-2-[(tetrahydropyran-2-yl)oxymethyl]pyridine (400 m g 14.6 mmol) prepared following the procedure given for Example 11 part a in dimethylformamide (5 ml) was added. The mixture was heated at 80° C. for 24 h then in a sealed tube at 120° C. for 4 h. The solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), and evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with 5% methanol/dichloromethane to give the title-compound (280 mg, 73%), 1H NMR (250 MHz, CDCl3), δ 1.5-1.8 (6H, m, 3 of CH2), 3.58 (1H, m, CH2O), 3.93 (1H, m, CH2O), 4.66 (1H, d, J=14.1 Hz, CH2O), 4.82 (1H, m, CH), 4.90 (1H, d, J=14.1 Hz, CH2O), 7.19 (1H, br s, Ar—H), 7.24 (1H, d, J=8.2 Hz, Ar—H), 7.43 (1H, dd, J=7.6 Hz and 7.1 Hz, Ar—H), 7.64 (1H, t, J=1.2 Hz, Ar—H), 7.83 (1H, t, J=7.9 Hz, Ar—H), 8.35 (1H, s, Ar—H); MS (ES30) m/e 260 [MH]+.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=[CH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 4,4-difluorocyclohexan-1-one (1.0 g, 7.46 mmol, 1.00 equiv) and (carbethoxymethylene)triphenylphosphorane (3.9 g, 24.05 mmol, 1.50 equiv) in THF (20 mL) was stirred under argon overnight at 65° C. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the crude residue was purified using flash column chromatography (silica gel, EtOAc/petroleum ether (1:10)) to yield 1.5 g (97%) of a colorless oil. 1H-NMR (400 MHz, CDCl3): δ ppm 5.75 (s, 1H), 4.18 (m, 2H), 3.06 (t, J=6.8 Hz, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.11-1.99 (m, 4H), 1.33-1.26 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:29]([S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:27])=[O:28])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCNCc1ccccc1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: O=C(Br)CBr
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 4-tert-butyl-N-p-tolyl-benzenesulfonamide
Reaction SMILES: C[C@@H]1C[C@@H]([C@H](O)CC2C[C:16](=O)[NH:15][C:13](=O)C2)C(=O)[C@@H](C)C1.[CH2:21]([O:28][C:29]1C=C2C(=CC=1)C=C(C=O)C=C2)[C:22]1C=CC=CC=1.[CH:41]([C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH:48]([O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[CH2:47][CH2:46]2)=[O:42]>>[CH3:13][N:15]([CH2:22][CH2:21][O:28][CH2:29][CH:41]([C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH:48]([O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[CH2:47][CH2:46]2)[OH:42])[CH3:16]
Reactant: C[C@@H]1C[C@@H]([C@H](O)CC2CC(=O)NC(=O)C2)C(=O)[C@@H](C)C1
Reactant: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Reactant: O=Cc1ccc2cc(OCc3ccccc3)ccc2c1
Product: CN(C)CCOCC(O)c1ccc2c(c1)CCC2OC1CCCCO1

Procedure:
The same procedure as in (1) and (2) of Production Example 28 was repeated, except that the 6-benzyloxy-2-naphthaldehyde was replaced by 5-formyl-1-(tetrahydropyran-2-yloxy)indane, to obtain oily 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol (compound No. 294).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]=[O:12])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of 1.10 g (4.0 mmol) tert-butyl N-(tert-butoxycarbonyl)-L-homoserinate (prepared according to J. Org. Chem. 1988, 53, 1900-1903) in dichloromethane (50 mL) was added pyridine (0.97 mL, 12.0 mmol), followed by 2.55 g Dess Martin periodinane (6.0 mmol), at room temperature. The mixture was stirred 90 min at room temperature prior to being diluted with ethyl acetate (40 mL). The mixture was washed with 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and then evaporated. The crude product (1.09 g, quantitative yield) was used immediately without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].B(F)(F)F.O(CC)CC.[N+](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-]>CCOCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCC)CCC1=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid ethyl ester (20 g, 117 mmol) was dissolved in 120 mL Et2O and cooled to −30° C. BF3-OEt2 (14.8 mL) and ethyl diazoacetate (16 mL, 152 mmol) were added simultaneously (each in 15 mL Et2O) over the course of 30 minutes, maintaining an internal temperature of approximately −20° C. The reaction was warmed to room temperature and stirred for 3 hours after which time the reaction was quenched carefully with 30% K2CO3 (60 mL). The organic layer was dried over K2CO3 and concentrated to give 30.4 g of the subtitle compound.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:21](Cl)(=[O:23])=[O:22])=[CH:16]2.C(N(C(C)C)CC)(C)C.ClC1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:21]([N:3]1[CH2:4][CH:5]3[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]3)[CH2:2]1)(=[O:22])=[O:23])=[CH:16]2
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Reactant: C1CC2CCC1CNC2
Agent: O=S(=O)(Cl)c1cccc2c(Cl)cccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CC2CCC(CC2)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from the coupling of 3-azabicyclo[3.2.2]nonane and 5-chloro-2-naphthalenesulfonyl chloride. 3-Azabicyclo[3.2.2]nonane (0.31 g, 2.5 mmol) and diisopropyl ethyl amine (1.0 ml, 5.7 mmol) were dissolved in 10 ml chloroform. 5-Chloro-1-naphthalenesulfonyl chloride (0.50 g. 1.9 mmol) in 20 ml chloroform was added dropwise to the solution. After stirring overnight, the solution was washed with saturated sodium bicarbonate solution and brine. Drying over magnesium sulfate and evaporation followed by recrystallization with isopropyl ether/methanol gave 0.50 g (76% yield) of a yellow solid: mp 138°-139° C.; 1H NMR (CDCl3): 8.39 (d, J=8.9, 1 H, H3), 8.33 (d, J=1.7, 1 H, H1), 7.91-7.84 (m, 2 H, H4 and H6), 7.72 (d, J=7.5, 1 H, H8), 7.52 (t, J=7.9, 1 H, H7), 3.31 (d, J=4.2, 4 H, N (CH2R)2), 2.09 (s, 2 H, N(CH2CHR)2), 1.75-1.61 (m, 8 H, alkyl H's); anal calcd for C18H20 2 NO2SCl; C, 61.79; H, 5.76; N, 4.00; found: C, 61.89; H, 5.80; N. 4.08.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:10]([NH:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)NN1CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a pyridine solution (500 ml) of 1-aminohydantoin hydrochloride (50 g, 0.3 mole) was added cinnamoyl chloride (53 g, 0.3 mole). The stirred mixture was heated on the steam bath for 5 hours, then poured into ice water. After standing overnight, the precipitated product was removed by filtration and washed thoroughly with water. After drying, the crude white product weighed 60 g (74%). Several recrystallizations from methanol provided analytical material which melted at 276°-278°.
Reaction SMILES: C[O-].[Mg+2:3].C[O-].[O-:6][CH2:7][CH3:8].[Mg+2].[O-:10][CH2:11][CH3:12].[C:13](=[O:15])=[O:14]>C(O)C>[CH2:7]([O:6][C:13](=[O:14])[O-:15])[CH3:8].[CH2:11]([O:10][Mg+:3])[CH3:12]
Reactant: [Mg+2]
Reactant: O=C=O
Reactant: CC[O-]
Agent: C[O-]
Solvent: CCO
Product: CCOC(=O)[O-]
Product: CCO[Mg+]

Procedure:
In addition to solubilizing dried magnesium methoxide I have found it possible to solubilize magnesium ethoxide, which is virtually insoluble in ethanol, through addition of carbon dioxide to produce the extremely soluble ethoxy magnesium ethyl carbonate.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].O1[CH2:20][CH2:19]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:20]=[CH:19][N:7]=[CH:6][C:2]=1[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Nc1scnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Nc1scnc1-c1cnccn1
Temperature: 140 °C
Yield: 62 %

Procedure:
A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (420 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol) and 2-tributyl-stannylpyrazine (930 mg, 2.5 mmol) in anhydrous dioxane (4 mL) was heated to 140° C. in a microwave reactor for 2 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes) to give the desired product (260 mg, 62%). 1H NMR (CDCl3) δ11.10 (s, 1H), 9.47 (d, J=1.4 Hz, 1H), 8.52 (t, J=2.0 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.40 (s, 1H), 1.58 (s, 9H); MH+ 279.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3cnccc3c2n1CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 226-230° C. Analysis: Calculated for C14H21N5+1.75 H2O: %C, 57.81; %H, 8.49; %N, 24.07; Found: %C, 57.89; %H, 8.04; %N, 23.45.
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]3[CH2:16]CC[C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1[C:20](O)=[O:21]>>[CH3:20][O:21][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2
Product: COc1cccc2c1C(=O)N(C)CC(=O)N2

Procedure:
(S)-6-methyl-1,2,3,11a-tetrahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepine-5,11(10H)-dione by reaction with L-proline. M.p. 207.6°-209.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:30].O1CCOCC1>O1CCOCC1>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(5-(4-fluorophenylsulfonyl)pyrimidin-2-yl)piperazine-1-carboxylate (100 mg, 0.237 mmol) in dioxane was added 4 M HCl/dioxane (6 mL). The mixture was stirred at RT for 3 hrs and concentrated to afford the title compound as a yellow oil, which was used into the next step without further purification. MS (ES+) C14H15FN4O2S requires: 322. found 323 [M+H]+.