Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35](O)=[O:36])=[CH:28][C:22]=3[C:23]=2[C:24](=[O:27])[NH:25][CH3:26])=[CH:15][CH:14]=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>CN(C=O)C.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:31]=[CH:30][C:29]([C:32]4[CH:40]=[CH:39][CH:38]=[C:34]([C:35]([N:8]5[CH2:9][CH2:10][CH2:11][CH:7]5[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:36])[CH:33]=4)=[CH:28][C:22]=3[C:23]=2[C:24]([NH:25][CH3:26])=[O:27])=[CH:15][CH:14]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N4CCCC4c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
2-Phenylpyrrolidine (20 mg, 0.14 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight. The reaction was then diluted with MeOH, filtered, and purified by prep HPLC. Concentration afforded the title compound (21 mg, 78% yield) as a light pink solid. 1H NMR (˜3:2 ratio of amide rotamers, 500 MHz, DMSO-d6) δ ppm 8.44-8.56 (m, 1H) 7.96-8.07 (m, 2H) 7.74-7.89 (m, 3H) 7.56-7.67 (m, 2H) 7.30-7.45 (m, 5.4H) 7.16-7.29 (m, 2.6H) 7.09 (d, J=7.02 Hz, 1H) 5.19 (t, J=6.71 Hz, 0.6H) 4.98 (d, J=6.41 Hz, 0.4H) 3.75-3.92 (m, 1.4H) 3.53-3.64 (m, 0.6H) 2.87 (m, 3H) 2.40 (dd, J=12.36, 6.56 Hz, 0.6H) 2.30-2.30-2.38 (m, 0.4H) 1.73-1.92 (m, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.86 min, (ES+) m/z (MH+)=519. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.38 min, purity=99%; column: Waters Xbridge Phenyl column 3.5 μm 4.6×150 mm, Rt=13.01 min, purity=99%.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:37])([F:36])[F:35])[N:17]=2)[CH2:10][CH2:9]1.CO.O.[Li+].[OH-]>CO>[N+:22]([C:21]1[C:16]([NH:15][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])[CH2:9][CH2:10]2)=[N:17][C:18]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])=[N:19][CH:20]=1)([O-:24])=[O:23]
Reactant: COC(=O)CCCNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-butyric acid methyl ester (39 mg, 0.072 mmol) in 6:1 MeOH/water (0.7 mL) was added LiOH (9 mg, 0.375 mmol) and the mixture stirred at room temperature overnight. The resulting suspension was diluted with MeOH (1 mL) and stirred at room temperature for a further 2 h. The reaction mixture was concentrated in vacuo and the remaining aqueous residue treated with 2 N HCl until the mixture reached pH 5-6. The resulting solid was filtered and washed with water. The material was subjected to semi-preparative to separate the title compound [7 mg, 13%, m/z 527 (M+1)+] and 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)pyrrolidin-2-one [15 mg, 41%, m/z 509 (M+1)+].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[C:7]([C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][C:12]([CH3:18])=[C:11]([CH3:19])[CH:10]=2)=[O:8].[N-]=[N+]=[N-]>C(O)C>[N:1]([C:16]1[C:15]([C:14]2[C:9]([C:7](=[O:8])[CH:6]=1)=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)=[O:17])=[N+:2]=[N-:3]
Reactant: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(N=[N+]=[N-])=CC2=O

Procedure:
An aqueous solution of sodium azide (4.4 g; 0.068 mole) was added at once to a refluxing suspension of 2-bromo-6,7-dimethyl naphtho-1,4-quinone (13.8 g; 0.052 mole) in ethanol (130 ml) and the resulting red solution refluxed for a further 2 mins. After cooling in ice the precipitated azide was separated, washed well with water and recrystallised from ethanol as an orange-red solid, m.p. 116°-119° C. (d).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 42.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methylbenzothiazole (84 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 66 mg (43%) of the title compound as an amorphous solid. mp 134°-142°. FDMS: m/e =408. α[D]589 =+62.80 (c=0.74, chloroform).
Reaction SMILES: [CH3:1][C@:2]([OH:17])([CH2:15][CH3:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].BrBr>C(Cl)Cl.[F-].[K+].CCOCC>[OH:17][C@@:2]([CH3:1])([CH2:15][CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC[C@](C)(O)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of the crude product from Step 7 (7 g) and (Bu3Sn)20 (30 mL) in 150 mL of CH2Cl2 cooled at 10° C. was added a solution of Br2 (9.3 g in 30 mL of CH2Cl2). After stirring at r.t. for 30 min. the mixture was diluted with a solution of KF (500 mL, 3N) and 500 mL of Et2O. The solid generated was removed by filtration and the filtrate was separated. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give 5 g of the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:22][OH:23])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]1[C:19]([OH:21])=[O:20].[C:24]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O.Cl.[Na+].[Cl-]>[Cl-].[Na+].O.O.CN1C(=O)CCC1>[OH:1][CH:2]([CH2:22][OH:23])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]1[C:19]([O:21][CH3:24])=[O:20]
Reactant: O=C([O-])O
Reactant: O=C(O)c1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Temperature: 0 °C

Procedure:
A reactor was charged with 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 6 (4.302 kg, 13.47 mol) followed by charging with NaHCO3 (1.69 kg, 20.09 mol) and 242 g of deionized water. To this was added 21.4 kg of NMP and the mixture was stirred and temperature brought to 28-35° C. Dimethyl sulfate (2.34 kg, 18.30 mol) was added dropwise via an addition funnel to the reaction mixture over 1-3 hours keeping the temperature at 28-33° C. The slurry was agitated at this temperature for 14 h. When deemed complete, the reaction mixture was cooled to 5° C. or below and the mixture was neutralized to pH 6 by the addition of HCl (561 mL of conc HCl in 2806 g of deionized water). The reaction vessel was slowly charged with cold 20% brine solution composed of 8.7 kg NaCl, 20 kg of deionized water and 14.8 kg of ice at a maximum temperature of 10° C. The mixture was agitated at 0-10° C. for 2.5 h. The slurry was filtered under vacuum and the cake washed with 15 kg of deionized water two times. The wet solid product was dried at 45-55° C. under vacuum until constant weight was obtained. The desired product methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 7 was obtained as a light yellow solid (3.77 kg, 99.42% purity by HPLC, 84%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J=7.5 Hz, 1H), 7.36 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.23 (d, J=5.4 Hz, 1H), 5.10 (Abq, J=10.8 Hz, 2H), 4.85 (m, 1H), 3.98 (dd, J=14.3, 2.4 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=14.3, 9.0 Hz, 1H), 3.58 (m, 1H), 3.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[C:10]1=[O:22].C([O-])([O-])=O.[K+].[K+].[CH2:29](Cl)[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOCC>[CH2:31]([O:30][CH2:29][N:14]1[C:13]2[C:12](=[O:20])[N:11]([CH3:21])[C:10](=[O:22])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:17]=2[N:16]=[C:15]1[CH2:18][CH3:19])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCOCc1ccccc1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2-c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1nc2c(c(=O)n(C)c(=O)n2-c2ccc(Cl)cc2Cl)n1COCc1ccccc1
Temperature: 45 °C
Yield: 65 %

Procedure:
3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione (6.00 g, 17.69 mmol), prepared according to the procedure in example 1, was dissolved in anhydrous DMF (80 mL). K2CO3 (6.11 g, 44.23 mmol), Bu4NI (1.31 g, 3.54 mmol) and BOMCl (4.4 mL, 31.84 mmol) were added and the reaction mixture was heated at 45° C. for 50 min. The reaction mixture was cooled to rt and was stirred with saturated aqueous NaHCO3 (180 mL) for 30 min. The mixture was poured into a separatory funnel containing ether (600 mL). The organic layer was washed with H2O (4×80 mL), brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexanes) to give 7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione (5.28 g, 65% yield) as an amorphous solid: 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=2.2 Hz, 1H), 7.42 (dd, J=8.4, 2.2 Hz, 1H), 7.37-7.26 (m, 6H), 5.86 (ABq, JAB=11.0, Δυ=39.7 Hz, 2H), 4.72 (s, 2H), 3.46 (s, 3H), 2.79 (q, J=7.7 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H); LRMS (APCI) m/e 459.0 [(M+H)+, calcd for C22H21N4O3Cl2 459.1].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:21]([OH:26])([CH2:24][CH3:25])[C:22]#[CH:23])[CH3:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][C:21]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)(CC)CC
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)(C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2)CC

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 2 hours with 1.40 g (12.5 mmol) of 3-ethyl-1-pentyn-3-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-3-(3-ethyl-3-hydroxy-1-pentynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 186°-188°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.[C:26]1([C:32]2[O:36][C:35](=[S:37])[NH:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[S:37][C:35]1[O:36][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:33][N:34]=1
Reactant: S=c1[nH]nc(-c2ccccc2)o1
Reactant: O=c1cnn(-c2cc(Cl)c(C(O)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: CS(=O)(=O)O
Product: O=c1cnn(-c2cc(Cl)c(C(Sc3nnc(-c4ccccc4)o3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
A mixture of 2-[3,5-dichloro-4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.005 mol) and 5-phenyl-1,3,4-oxadiazole-2(3H)-thione (0.006 mol) in methanesulfonic acid (20 ml) was stirred for 18 hours at RT. The reaction mixture was poured out into water/ice (150 ml), and the resulting precipitate was filtered off, stirred in water, treated with NaHCO3 and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97.5/2.5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 1 g of (±)-2-[3,5-dichloro-4-[(4-chlorophenyl)[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (comp. 406).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[N:17]1([CH2:22][CH2:23][C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=[CH:18]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:24](=[O:25])[CH2:23][CH2:22][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:4]=2[CH:3]=1
Reactant: O=C(O)CCn1ccnc1
Reactant: O=S1c2ccccc2Nc2cc(Cl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
A mixture of 25 g of 2-chloro-phenothiazine-5-oxide, 14 g of 3-(imidazol-1-yl)-propionic acid, 20.6 g of dicyclohexylcarbodiimide and 250 ml of tetrahydrofuran is stirred for 1 hour at 0° and then for 2 hours at 30°. It is worked up in the customary manner to give 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, melting point 148°-149°.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[C:17]1([NH:16][C:15]([C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:27])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1(C(=O)Nc2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1(C(=O)Nc2cccc3c2CCCC3)Cc2ccccc2C1
Reaction time: 14 h
Yield: 85.2 %

Procedure:
A 100 mL flask containing 2-(5,6,7,8-tetrahydro-napthalene-1-yl-carbamoyl)-indan-2-carboxylic acid ethyl ester (0.23 g, 0.63 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH (67 mg, 1.58 mmol). After 14 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜6 mL). The contents of the flask are poured into a reparatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by pumping to constant weight to give 0.18 g of white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[CH2:19][N:18]([C:20](=[O:22])[CH3:21])[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=4[CH:15]=[CH:14][C:13]=3[CH:27]=2)O1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Br)[N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:29][C:30]1[N:31]=[C:32]([C:9]2[CH:10]=[CH:11][C:12]3[CH2:19][N:18]([C:20](=[O:22])[CH3:21])[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=4[CH:15]=[CH:14][C:13]=3[CH:27]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C=Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)N1Cc2ccc(-c3cccc(Br)n3)cc2C=Cc2ccccc21
Temperature: 80 °C
Yield: 60 %

Procedure:
A 2 mL conical vial was charged with 1-[9-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-6H-dibenzo[b,f]azocin-5-yl]-ethanone (prepared by the method described in Example 2A starting with 2)(30 mg, 0.08 mmol), 2,6-Dibromo-pyridine (39 mg, 0.18 mmol) and Pd(PPh3)4 (9 mg). The vial was evacuated and purged with argon. EtOH (0.5 mL) and toluene (0.5 mL) were added, followed by 2M aqueous Na2CO3 (0.036 mL, 0.072 mmol). The reaction was heated to 80° C. until disappearance of the starting material was noted. The reaction was cooled to room temperature and concentrated. The product was purified by reversed-phase HPLC to afford Example 206A (18.5 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-3-pyridinamine (5 g) was dissolved in pyridine (150 ml) and the reaction was cooled to 0° C. in an ice-bath and stirred for 5 min. Benzenesulfonyl chloride (1.86 ml) was added dropwise and the reaction was stirred at 0° C. for 3 hr. Further benzenesulfonyl chloride (1.86 ml) was added and the reaction continued stirring for 1 hr. The reaction was neutralised with 2 M HCl and extracted with DCM (60 ml) then evaporated to dryness. The residue was dissolved in DCM and preadsorbed on fluorosil then purified by column chromatography on silica, eluting with 1-5% MeOH/DCM, to give the title compound (8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc4ncccc34)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 5-hydroxyquinoline (111 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1.0 N aqueous sodium hydroxide solution (40 ml) and allowed to stir at ambient temperature for a few minutes. The resulting precipitate was filtered off, washed with water and air dried for a short while. The damp solid was dissolved in dichloromethane, filtered through phase separating paper and the filtrate evaporated under vacuum. The residue was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-5-yloxy)-quinazoline (178 mg, 59%).
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.BrC[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].P(OCC)(OCC)OCC>>[C:12]1(=[O:21])[N:11]([CH2:10][P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: COP(OC)OC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: CCOP(OCC)OCC
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC

Procedure:
Reaction of N-bromoethylphthalmide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.