Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][C:38]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)=[O:39])[CH:31]=[CH:30]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([NH:37][C:38]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[O:39])[CH:31]=[CH:30]4)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4cccs4)ccc3c2)OC1(C)C
Reactant: CN(C)CCCNc1nccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCCNc1nccc2c(-c3ccc4cc(NC(=O)c5cccs5)ccc4c3)cccc12
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a microwave vial containing 5-bromo-N-(3(dimethylamino)propyl) isoquinolin-1-amine (Step 4, 0.055 g, 0.2 mmol) in 1,4-Dioxane (2 mL), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-2-carboxamide (0.076 g, 0.2 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), along with 2 M Potassium Carbonate (0.5 mL, 1 mmol). The mixture was placed into CEM Microwave for 10 minutes at 80° C., while supplying 60 Watts of energy via power-max. Then mixture was diluted with DCM and H2O, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. The crude was purified on reverse-phase HPLC. This gave a light yellow amorphous solid after drying, which was titled product (0.026 g, 0.03 mmol). MS (ESI pos. ion) m/z: 481 (M+H). Calc'd Exact Mass for C29H28N4OS: 480
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:28]=[CH:27][C:9]2[C:10]3[C:25](=[O:26])[NH:24][CH2:23][C:11]=3[CH2:12][N+:13]([O-])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]2[C:10]3[C:25](=[O:26])[NH:24][CH2:23][C:11]=3[CH2:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:7]=1
Reactant: O=C1NCC2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: O=C1NCC2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In one portion, 2 ml (2.3 mmol) of phosphorous trichloride were added to a solution of 1.0 g (2.7 mmol) of 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepine-1(2H)-one-5-oxide in 200 ml of methylene chloride and refluxed for 1 hour. The mixture was concentrated at reduced pressure. The residue was dissolved in methylene chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark red residue. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one as pale yellow prisms solvated with 0.5 mole ethyl acetate, mp 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH:14]=[O:15])=[CH:17]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (10 ml) was added 3-formylindole (623 mg) and potassium carbonate (593 mg), the mixture was heated at 90° C. for 1.5 hrs. The reaction was cooled to room temperature and diluted with water (200 ml) and extracted with ether (200 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a pale yellow crystaline material, m.p. 167-169° C.
Reaction SMILES: [N:1]1([C:6]2[C:7]3[NH:14][CH:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O[Li].O.CO>C1COCC1.O>[N:1]1([C:6]2[C:7]3[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1c[nH]c2c(-n3cccn3)ncnc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c2c(-n3cccn3)ncnc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate 49 (2.0 g, 7.8 mmol) in THF (45 mL) was added a solution of LiOH.H2O (1.3 g, 31 mmol) in H2O (30 mL) and the reaction was stirred at 100° C. for 16 h. Additional LiOH.H2O (2.0 g, 48 mmol) was added, heating continued for 2 h, MeOH was added (10 mL) and heating continued at 100° C. for 1d. The reaction mixture was cooled, filtered, concentrated to ˜20% volume and neutralized with ice and conc HCl. The white precipitate that formed was collected by filtration and washed with brine, H2O, EtOAc, and Et2O to yield 50 (quantitative), which was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 12.07 (br s, 1H), 8.89 (br s, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 8.09 (br s, 1H), 6.76-6.73 (m, 1H);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[CH:35](OCC)(OCC)OCC>C(O)(=O)C>[CH3:30][C:4]1[C:5]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=[C:2]([N:1]2[CH:35]=[N:33][N:32]=[N:31]2)[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnn2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-((1R,2S)-2-{-[(5-amino-3-methylpyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (1.20 g, 2.93 mmol) in acetic acid (50 mL) was added sodium azide (762 mg, 11.72 mmol) followed by triethyl orthoformate (1.95 mL, 11.72 mmol) and the resulting solution was heated to 60° C. and stirred for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between NaHCO3 and ethyl acetate. The aqueous was again extracted with ethyl acetate (100 mL). The organics were combined, washed by brine, dried on sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (40 M+ silica gel) using a gradient eluant of 0-100% ethyl acetate in hexane (800 ml) to afford the title compound. LC/MS (m/z): 463 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:22](=O)=[O:23]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]2[C:4]=1[C:22](=[O:23])[O:13][CH:6]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2ccccc2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc2c1C(=O)OC2c1ccccc1

Procedure:
To 3-methoxybenzhydrol (42.8 g.) in dry ether (800 ml.) is added 2.3 M. n-butyl lithium in hexane (250 ml.), dropwise with stirring under nitrogen. The deep red solution is stirred and heated under reflux for 2 hours and then poured into a stirred slurry of a large excess of solid carbon dioxide in ether and stirred until no carbon dioxide remains. The resulting suspension is extracted with water, the extract is acidified with concentrated hydrochloric acid, the precipitate is filtered off, washed with water, dried, and recrystallised from isopropanol to give 7-methoxy-3-phenylphthalide, m.p. 135°-138°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Cl[C:34]1[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:34]4[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)nn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of [(3S,4R)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (186 mg, 0.40 mmol) in DMF (2 mL) was added 6-chloro-3-pyridazinecarbonitrile (67 mg, 0.48 mmol) and N,N-diisopropyl ethyl amine (208, 1.21 mmol). The resulting dark brown solution was stirred for 3 h at 80° C. After cooling to ambient temperature the reaction mixture was diluted with ethyl acetate (15 mL) and washed with aqueous sodium carbonate (1M, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (167 mg, 73%) as a white foam. MS m/e: 563.3 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=O)[NH:12][CH:11]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O.Cl>C(#N)C.O1CCOCC1>[Cl:23][C:13]1[N:12]=[CH:11][C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cc2c[nH]c(=O)c3cccnc23)cn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Temperature: 25 °C

Procedure:
396 mg (1.48 mmol) of 8-[(6-methoxy-pyridin-3-yl)-methyl]-6H-[1,6]naphthyridin-5-one in 24 ml of acetonitrile are mixed, whilst excluding air, with 1.4 ml (15 mmol) of phosphorus oxychloride and 0.78 ml of 4 N HCl in dioxane and stirred for 96 h at 65° C. After cooling to RT, partial concentration by evaporation takes place on a RE, then 40 ml of ice water and 10 ml of NH3 solution are added and extraction carried out 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contaminated with a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine); FAB-MS: (M+H)+=286; HPLC(gradient20-100) tRet=10.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:19].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]Cl)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.C(O)(=O)C>[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:35][CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16])[CH3:19]
Reactant: CCc1ccccc1N
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCCN3CCOCC3)c(OC)cc12
Temperature: 100 °C
Yield: 17.6 %

Procedure:
A mixture of 4-Chloro-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.056 g, 0.22 mmol), 2-ethylaniline (32 μL, 0.26 mmol) and acetic acid (10 μL) in ethanol (5 ml) was heated at reflux for four hours. The solvents were removed by reduced pressure and the residue was chromatographed on silica using methanol as eluent. The product was dissolved in DMSO (5 ml), morpholinopropylchloride (0.018 g, 0.11 mmol) and Cs2CO3 (0.090 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 hours. After cooling the mixture was poured on water and the water phases were extracted with methylenechloride. The residue was chromatographed on silica using methylenechloride/methanol (9/1–1/1) as eluent, affording 9 mg (9% yield) of the titled compound. 1H NMR (CDCl3): δ 11.05 (1H, s); 8.96 (1H, s); 7.35 (1H, s); 7.32 (1H, dd); 7.12 (2H, m); 6.91 (1H, dd); 6.74 (1H, s); 4.22 (2H, m); 3.68 (4H, m); 3.25 (3H, s); 2.80 (2H, m); 2.52 (2H, q); 2.44 (4H, m); 2.08 (2H, m); 1.30 (3H, t).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)CNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 65 °C

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.09 g, 3.64 mmol), methyl glycinate hydrochloride (0.68 g, 5.46 mmol) and TEA (10.10 g, 10.92 mmol) were dissolved in a mixture of MeCN (10 mL) and DMF (5 mL) and the reaction mixture was stirred at 65° C. over night. The reaction mixture was evaporated and the residue was diluted with saturated aqueous NaHCO3 and the mixture was extracted with DCM. The organic phases were combined, dried over MgSO4, filtered and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[CH:2][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=439.1, tR (minutes, Method G)=2.76. [α]D20=+3.18 (c=6.38 mg/mL,CHCl3)
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[CH3:26].CN(C)C=O.C(N(CC)CC)C>O1CCCC1>[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][C:10]3[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=3)=[N:20][C:21]#[N:22])=[CH:23][CH:24]=2)=[O:36])=[CH:30][CH:29]=1)[CH3:26]
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc(NC(=O)Nc2ccc(CNC(=NC#N)Nc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (100 mg, 0.380 mmol) and 1-ethoxy-4-isocyanato-benzene (61 mg,, 0.39 mmol) were dissolved in and mixture of N,N-dimethylformamide (2.0 mL).and tetrahydrofuran (1.0 mL). Triethylamine (0.060 mL, 0.390 mmol) was added. The reaction mixture was shaken at room temperature for 12 hours. The solvent was removed in vacuo to give the title compound (yield=85%). 1H NMR (DMSO-d6, ppm): 8.34 (br, s, 2H); 7.41-7.21 (m, 10H); 6.82-6.76 (m, 2H); 4.43 (s, 2H); 3.93 (dq, 2H); 1.28 (dt, 3H).
Reaction SMILES: C(OC=[C:5]([C:11](OCC)=O)[C:6]([O:8]CC)=O)C.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([N:22]2[C:6](=[O:8])[CH2:5][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CO
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 175.9 %

Procedure:
Diethyl ethoxymethylene-malonate (5.20 ml; 26 mmol) was added rapidly to 2.75 ml (28 mmol) of phenylhydrazine in 15 ml of methanol and the resulting mixture was refluxed for 4 hours. The mixture was cooled and concentrated in vacuo, and the residue was crystallized from ethanol to afford 5.82 g (97%) of 2,4-dihydro-2-phenyl-4-ethoxycarbonyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =H; R3 =C(O)OEt) as white needles, m.p. 106°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[Cl:17].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:48]([NH:51][C:52](=[O:68])[C:53]1[CH:58]=[C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:56]=[CH:55][C:54]=1[NH:66][CH3:67])([CH3:50])[CH3:49]>C(Cl)Cl.C1COCC1>[Cl:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[O:7][CH2:6][C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([N:66]([CH3:67])[C:54]1[CH:55]=[CH:56][C:57]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:58][C:53]=1[C:52]([NH:51][CH:48]([CH3:49])[CH3:50])=[O:68])=[O:14]
Reactant: CNc1ccc(Oc2ccccc2)cc1C(=O)NC(C)C
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2Cl)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: N#CC(Cl)(Cl)Cl
Product: COc1ccc(COc2ccc(C(=O)N(C)c3ccc(Oc4ccccc4)cc3C(=O)NC(C)C)cc2Cl)cc1OC
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A slurry of 1B (28 mg, 0.09 mmol) and trichloroacetonitrile (0.009 mL, 0.09 mmol) in CH2Cl2 (1 mL) at room temperature was treated with a solution of triphenylphosphine (22 mg, 0.09 mmol) in THF (0.25 mL). The reaction mixture was stirred for 30 minutes and additional trichloroacetonitrile (0.009 mL, 0.09 mmol) and triphenylphosphine (22 mg, 0.09 mmol) were added. The resulting solution was treated with 44B (16 mg, 0.06 mmol) in CH2Cl2 (0.5 mL). The stirring was continued for 2 hours, and then the reaction concentrated to dryness. The residue was purified by chromatography (SiO2, 50% to 75% EtOAc in hexanes) to afford 44C (31 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: CCc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1

Procedure:
From 2,6-dichloro-3-nitropyridine and 4-ethylaniline, prepared in a similar manner as the one described in Example 1.21 with the exception that the reaction was performed at 65° C., the title compound was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[C:39]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(N(CC)CC)C>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:49]4[CH2:48][CH2:47][N:46]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:51][CH2:50]4)=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-boc-piperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=234-235° C. 1H NMR 400 MHz (DMSO-d6) δ 8.44 (d, J=7.6 Hz, 1 H), 8.18 (s, 1 H), 7.72 (d, J=7.6 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.46-7.34 (m, 3 H), 7.27-7.21 (m, 3 H), 7.15-7.13 (m, 2 H), 6.90 (d, J=7.6 Hz, 1 H), 4.81 (t, J=7.2 Hz, 1 H), 3.49-3.47 (m, 4 H), 3.23-3.18 (m, 1 H), 3.07-3.01 (m, 1 H), 2.83-2.79 (m, 2 H), 2.65-2.61 (m, 2 H), 1.48 (s, 9 H). LCMS 630 (M+H).
Reaction SMILES: FC(F)(F)C([O-])=[O:4].FC1C=CC(C2C(C[P+](CCCC)(CCCC)CCCC)=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=2)=CC=1.[Si:44]([O:51][C@H:52]1[CH2:57][C:56](=[O:58])[O:55][C@H:54]([CH:59]=[O:60])[CH2:53]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].O>C1(C)C=CC=CC=1>[Si:44]([O:51][C@@H:52]1[CH2:53][C@@H:54]([CH:59]([OH:4])[OH:60])[O:55][C:56](=[O:58])[CH2:57]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Reactant: O=C([O-])C(F)(F)F
Agent: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)tributylphosphonium 2,2,2-trifluoro-acetate (50.4, 77 mmol) at room temperature in dry toluene (800 mL) sodium hexamethyldisilazane (NaHDMS) in toluene (130 mL of 0.6 M, 77 mmol) was added portionwise in 10 minutes. The reaction mixture was stirred for 60 min and treated at room temperature with a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (20 g, 77 mmol) in 2.5 L of dry toluene obtained by dissolution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (21.4 g, 77 mmol) in toluene and removal of released water. After 24 hours of stirring at room temperature the solution was treated with saturated ammonium chloride solution or water. The aqueous phase was extracted with methyl t-butyl ether (2×2 L), and the combined organic layers dried and concentrated to give oily residue with 25-40% HPLC area of RSVLTBS.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].C(N(CC)CC)C.[N-:15]=[N+:16]=[N-:17].[Na+]>C(Cl)Cl.O>[N:15]([CH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)CCBr
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CCN=[N+]=[N-]
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 4-bromo-2-methylbutan-2-ol (0.4 g, 2.4 mmol) and triethylamine (1 ml, 7 mmol, 3 eq.) in CH2Cl2 (15 ml) was added sodium azide (0.47 g, 7 mmol, 3 eq.) in H2O (5 ml) and the mixture was allowed to stir overnight. The mixture was quenched with water and extracted with CH2Cl2 (3×50 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 65% yield (0.2 g). 1H NMR (300 MHz, DMSO-d6): δ 4.39 (br s, 1H), 3.40-3.32 (m, 2H), 1.15 (t, 2H), 1.23-1.04 (m, 6H).