Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>C1COCC1>[CH3:19][O:1][CH2:2][C@H:3]([N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
(R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9c) (5.88 g, 23.87 mmol) was dissolved in dry THF (25 mL) and hexamethyl-phosphoramide (30 mL) and the solution cooled to 0° C. Sodium hydride (60% in mineral oil, 1.15 g, 28.65 mmol) was added and after 10 minutes iodomethane (7.43 ml, 119.35 mmol) was added dropwise and the solution was warmed up slowly to room temperature and stirred over night. The reaction mixture was poured into ice/water, extracted with EtOAC, washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOAC in hexane) to give 3.92 g of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoine-1,3-dione (63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([O:17][CH2:18][CH3:19])=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[NH:34])[NH:32]O)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([O:17][CH2:18][CH3:19])=[N:11][C:10]=1[C:20]1[O:22][N:34]=[C:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(Cc1ccc(F)cc1)NO
Reactant: CCOc1nc(C(=O)O)c(OCc2ccccc2)c(=O)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOc1nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c(=O)n1C
Temperature: 100 °C

Procedure:
A mixture of 5-(benzyloxy)-2-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.5045 g, 3 mmol), 2-(4-fluorophenyl)-N-hydroxyacetimidamide (0.9190, 3.02 mmol), HATU (1.255 g, 3.3 mmol) and DIEA (0.5 mL) in 1,4-dioxane (20 mL) was heated at 100° C. for 6 h. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (10 mL), sat. NaHCO3 (10 mL), brine (10 mL), then dried (Na2SO4), filtered and concentrated to give a brown residue. This residue was purified by flash chromatography on a silica gel column using 7:3 Hexanes/EtOAc as eluant to afford the title compound product (0.68 g, 52% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.41-7.38 (2H, m), 7.30 (2H, dd, J=8.6, 5.2 Hz), 7.27-7.24 (3H, m), 6.99 (2H, t, J=8.6 Hz), 5.24 (2H, s), 4.52 (2H, q, J=7.0 Hz), 4.13 (2H, s), 3.47 (3H, s), 1.44 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C23H22N4O4F: 437.1625. found: 437.4719. Anal calcd for C23H21N4O4F: C, 63.29; H, 4.85; N, 12.83. found: C, 62.76; H, 4.84; N, 12.81.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7](S(C)(=O)=O)[CH:8]=[C:9]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH:10]=1)=[O:5])C.CO.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]([C:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[NH:7][CH:8]=2)[CH:39]=[N:38][CH:37]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(N=Cc2cccc(F)c2F)cn1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: O=C(O)c1cc(-n2cncc2-c2cccc(F)c2F)c[nH]1
Yield: 12.3 %

Procedure:
To a solution of 4-[(2,3-difluoro-benzylidene)-amino]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (500 mg, 1.40 mmol) in co-solvents of MeOH (10 mL) and DME (5 mL) was added TosMIC (410 mg, 2.10 mmol) and K2CO3 (390 mg, 2,82 mmol). The reaction mixture was heated under reflux for 2 hours and the solvents were removed by evaporation. The residue was treated with LiOH in THF/H2O at room temperature for 14 hours. After removal of the solvents by evaporation, the residue was acidified by 2N HCl solution. The crude product was then purified by HPLC to afford 50 mg desired product (12%). MS (ES−): m/e=288.0 (M−H); LC/Method A/2.45 min.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([OH:11])=O)[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>S(Cl)(Cl)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH:23]=2)=[O:11])[C:6]=1[O:7][CH3:8]
Reactant: COc1c(C(=O)O)csc1Br
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2csc(Br)c2OC)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
2-Bromo-3-methoxythiophene-4-carboxylic acid (0.429 g; 1.81 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (5 ml) and treated with dry triethylamine (0.25 ml;1.81 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.4 g; 1.8mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as white powder after trituration with Et2O (0.43 g;54%), mp=120-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (60 grams), the dimethyl acetal of 2-chloroacetaldehyde (25 grams) and sodium carbonate )21.2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150°C for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 105°C at 1 mm of Hg pressure.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21](S(C)(=O)=O)=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([C:18]3[CH:19]=[N:20][C:21]([C:1]#[N:2])=[N:22][CH:23]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(-c2cnc(S(C)(=O)=O)nc2)cc1OC1CCCC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of potassium cyanide (205 mg) in dry DMF (10 ml) was added the compound of Example 12 (1.0 g) and the reaction mixture stirred at room temperature for 3 hr then at 50° C. for 2 h. The reaction mixture was poured into a saturated NaHCO3 solution (2.5 g Na2 CO3 in 120 ml ice). The resulting yellow precipitate was filtered off and washed with water. Recrystallisation from EtOAc/hexane (1:2) gave the title compound (575 mg) as yellow needles (mp 121°-123° C.). Found C, 69.15; H, 5.73; N, 14.13. C17H17N3O2 requires C, 69.14; H, 5.80; N, 14.23%.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])=[N:5][CH:4]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl.C(OCC)(=O)C.O>[F:42][C:2]([F:1])([F:41])[C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])=[N:5][CH:4]=1
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncc(C(F)(F)F)[nH]1
Solvent: NCCN
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncc(C(F)(F)F)[nH]1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethyl]-amide (34 mg, 56.4 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (174 μL, 2.26 mmol) at 20° C. After 3 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (1 mL) and ethylenediamine (229 μL, 3.39 mmol) added. The mixture was stirred for 1 h, then diluted with ethyl acetate and water. The organic layer was washed with brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 12 g Analogix column, 0-10% methanol in dichloromethane, gradient over 30 min) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)ethyl]-amide (16 mg, 60%) as a light yellow solid. MS (M+H)+=473; 1H NMR (DMSO-d6) δ: 12.94 (d, J=3.0 Hz, 1H), 12.80 (br. s., 1H), 9.12 (s, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.50 (d, J=3.3 Hz, 1H), 8.42-8.49 (m, 1H), 7.72 (s, 1H), 7.67 (dd, J=9.8, 2.0 Hz, 1H), 7.00 (td, J=9.2, 2.3 Hz, 1H), 5.32-5.59 (m, 1H), 4.14 (s, 3H), 1.64 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19].N1C=CC=CC=1>C(Cl)Cl>[CH:14]([CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:17])[F:1])=[CH:5][CH:6]=1)[C:11]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Reaction time: 60 h
Yield: 24.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride (4.82 g) in methylene chloride (10 ml) is added to a methylene chloride solution (10 ml) of α-cyano-m-phenoxybenzyl alcohol (4.05 g) and pyridine (1.5 ml). The mixture is stirred for approximately 60 hours and filtered. The filtrate and the washings are evaporated and the residual oil (6.29 g) is purified on a silica column using 1:1 methylenechloride-hexane as an eluant. The solvent is evaporated and the residue treated with sodium borohydride. The resulting crude material is purified on a silica gel column to yield 2.01 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:23][CH2:21][C:20]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH3:19])=[O:22]
Reactant: CC(=O)c1c(C)cc(Oc2ccc(C(F)(F)F)cc2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (1.80 g, 5.84 mmol) in acetonitrile (11.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 2.82 g, 5.84 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,6-dimethyl-4-(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.16 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O[NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[NH:29].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:27]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(NO)c1ccccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccccn3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
To a mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (120 mg, 0.32 mmol) and of N-hydroxy-2-pyridinecarboximidamide (50 mg, 0.36 mmol) in EtOH (2 ml) was added a 21% (w/v) solution of sodium ethoxide in EtOH (0.225 ml, 0.62 mmol) and then heated in a sealed vial in a microwave oven at 140° C. for 10 min. The cooled mixture was evaporated to dryness and the residue partitioned between chloroform (5 ml) and saturated aqueous ammonium chloride (5 ml). The organic phase was evaporated to dryness and the crude product subjected to purification by MDAP. Product containing fractions were combined and evaporated to dryness. The product was triturated to a solid in a small amount of diethyl ether then dried to reveal the title compound as a white solid (44 mg, 31%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:30])[C@@H:23]([N:36]4[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]4)[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Reactant: OC1CCNCC1
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 78.3 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-17β-hydroxy-5α-androstane is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 78.3%, m.p.: 199°-201° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(Cl)n1
Reactant: C1COCCN1
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 225 °C
Yield: 71.7 %

Procedure:
6-Chloro-2-pyridinamine (1 g, 7.78 mmol) was dissolved in morpholine (6.80 ml, 78 mmol) and heated to 225° C. in a microwave reactor for 60 minutes (˜400 W; 5 mbar). The reaction was cooled to rt and concentrated. The crude product was taken up in DCM (50 mL). After filtration of white solids the crude product was concentrated and purified by silica gel column chromatography eluting with 20-50% EtOAc/hexanes to afford 1 g (5.58 mmol, 72%) of the title compound as a pale yellow solid. LC/MS: (M+H)+: 179.9.
Reaction SMILES: O=[C:2]([CH3:44])/[C:3](=[N:11]/[O:12][C@@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH2:14]1)/[C:4]([O:6]C(C)(C)C)=[O:5].S(Cl)(Cl)(=O)=O.[NH2:50][C:51]([NH2:53])=[S:52].CN(C)C1C=CC=CC=1>C(O)(=O)C.C(O)C>[NH2:53][C:51]1[S:52][CH:44]=[C:2](/[C:3](=[N:11]/[O:12][C@@H:13]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C@H:15]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:14]2)/[C:4]([OH:6])=[O:5])[N:50]=1
Reactant: NC(N)=S
Reactant: CC(=O)/C(=N/O[C@H]1C[C@@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OC(C)(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: Nc1nc(/C(=N/O[C@H]2C[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)C(=O)O)cs1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
tert-Butyl 3-oxo-(Z)-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(4-nitrobenzyloxycarbonyl)pyrrolidine-4-yloxyimino]butyrate (2.19 g, 3.56 mmol) in acetic acid (7 ml) was treated with sulphuryl chloride (2.89 ml, 4.81 g, 35.6 mmol) and the mixture was heated at 50° C. for 2.75 h. The mixture was evaporated under reduced pressure, and toluene added to the residue an the solvent evaporated. The was repeated a further three times. The residue was partially dissolved in ethanol (15 ml) and thiourea (271 mg, 3.56 mmol) was added, followed by N,N-dimethylaniline (0.9 ml, 860 mg, 7.1 mmol). Ethanol (15 ml) was added and the mixture was warmed to effect dissolution, the mixture was stirred at room temperture for 1.5 h, then warmed again to dissolve the material, and stirred a further 0.5 h. The ethanol was then removed by evaporation under reduced pressure and a mixture of water/ethyl acetate/n-butanol added. The pH was adjusted to 2 and the layers separated. The aqueous layer was again extracted with n-butanol (x2). The butanol extracts were combined and evaporated under reduced pressure. Ethanol was added to the residue and removed under reduced pressure, followed by toluene (x3) to leave a solid which was dried over P2O5 in vacuo to give the crude title compound (2.03 g); νmax (KBr) 3383, 1745, 1710, 1630, 1607, 1521, 1432, 1404 and 1347 cm-1.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].C(=O)=O.C(#N)C.[N:23]([CH:26]1[CH2:30][C:29](=[O:31])[CH:28]=[CH:27]1)=[N+:24]=[N-:25].FC(F)(F)C(O)=O>C(O)C>[N:23]([C@H:26]1[C@H:27]([C:5]([NH:4][C:1]([CH3:2])=[O:3])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:28][C:29](=[O:31])[CH2:30]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NC1C=CC(=O)C1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=C=O
Agent: [Na]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)[C@@H]1CC(=O)C[C@H]1N=[N+]=[N-]
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of diethyl acetamidomalonate (Aldrich, 1.25 g, 5.7 mmol) in ethanol (10 mL) under nitrogen was added freshly cut sodium metal (0.03 g, 1.4 mmol). The reaction mixture was stirred at room temperature until all sodium has dissolved. The reaction mixture was cooled to −40° C. (dry ice/acetonitrile) and a solution of 4-azidocyclopent-2-enone (0.7 g, 5.7 mmol) in ethanol (5 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at −40° C. for 30 min and quenched with trifluoroacetic acid (0.1 mL, 1.4 mmol). The solvent was removed in vacuo to furnish a white solid. Purification of the crude by flash column chromatography (60% ether in hexane) gave 1.2 g (63%) of trans-3-azido-4-[(methylcarbonyl-amino)bis(ethoxycarbonyl)methyl]cyclopentanone as a white solid, mp 121-122° C.
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]2>C(O)C.[Pd]>[OH:9][CH2:8][CH:7]1[CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH:3]1[NH:2][CH3:1]
Reactant: CCOC(=O)N1CC2CON(C)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC(CO)C(NC)C1

Procedure:
10 g (50 mmol) of ethyl 2-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate (Example H d)) are hydrogenated in 200 ml of ethanol on 3 g of Pd-on-active charcoal (10% of Pd) at 50° C. under 50 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[Na].[N-:20]=[N+:21]=[N-:22].[Cl-].[NH4+]>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:22][N:21]=[N:20][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium size azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](I)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.B([O-])O[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(OCC)(=O)C.O.O1CCOCC1>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(F)c(C#N)c(I)c1OC
Reactant: [O-]BOc1ccccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(F)c(C#N)c(-c2ccccn2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Under nitrogen, stirred dioxane (20 ml) at 80° C. was charged with 6-fluoro-2-iodo-3,4-dimethoxybenzonitrile from Example 1(a) (1.0 g, 3.3 mmol), tetrakis(triphenyl-phosphine) palladium(0) (0.19 g, 0.16 mmol), the pyridyl boronate from Example 1(b) (1.22 g, estimated to be 7.1 mmol), copper(I)iodide (0.25 g, 1.3 mmol), sodium carbonate (0.69 g, 6.5 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) and the resulting brown slurry heated to reflux. Further portions of the pyridyl boronate were added at the following times after the reaction had reached reflux: 0.61 g after 30 mins; 0.61 g after 1 hour; 0.61 g after 1 hour 30 mins; 0.61 g after 2 hours 30 mins; 0.61 g after 3 hours; and 0.30 g after 4 hours. After a total of 5 hours at reflux the reaction was allowed to cool to room temperature, water (10 ml) and ethyl acetate (20 ml) were added and the resulting mixture allowed to stir for 15 mins. After this time, the mixture was filtered through Arbocel™ filter aid and the pad washed with ethyl acetate (20 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (20 ml). The organic phases were combined and evaporated to a brown oil. Acetonitrile was added, the mixture warmed to reflux and left to cool to room temperature overnight. The resulting suspension was filtered to give a cream solid that was dried in vacuo overnight at 45° C. to give 0.42 g of the title product (49%).