Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].CS[C:24]1[NH:25][CH:26]=[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=2)[C:28](=[O:30])[N:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:24]3[NH:25][CH:26]=[C:27]([CH2:31][C:32]4[CH:33]=[N:34][C:35](=[O:38])[NH:36][CH:37]=4)[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CSc1nc(=O)c(Cc2cnc(=O)[nH]c2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Product: O=c1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Temperature: 150 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.380 mmol, 1.00 eq) and 2-methylsulfanyl-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.240 mmol, 0.63 eq) were dissolved in dry pyridine (300 μL) and stirred at 150° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP 1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-oxo-1,2-dihydro-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.041 mmol, yield: 11%, HPLC-MS/UV:[M+H]+=518.047; rt: 10.97 mins; purity: 85%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.80 (t, J=6.50, 2H), 3.19-3.22 (m, 2H), 3.41-3.52 (m, 2H), 5.39 (br.s., 1H), 6.33-6.64 (m, 1H), 6.99-7.10 (m, 2H), 7.22 (dd, J=9.24, J=3.42, 1H), 7.26-7.32 (m, 2H), 7.38-7.43 (m, 1H), 7.58-7.72 (m, 2H), 8.11 (br.s., 1H), 10.93 (br.s., 1H)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.I[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: ICC1CCOCC1
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(N(CC3CCOCC3)NC2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 140 °C

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.155 mmol), 4-(iodomethyl)-tetrahydro-2H-pyran (70 mg, 0.310 mmol), and Cs2CO3 (101 mg, 0.310 mmol) in DMF (1 mL) is heated in microwave at 140° C. for 30 min. After cooling, the mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi-preparative HPLC to give pure product as white powder. MS (ESI) m/z 421.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:19]1N=C[N:21]([C:24]([N:26]2C=NC=C2)=[O:25])[CH:20]=1.O1C=CN=C1N.CC#N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:26][C:24]1[O:25][CH:19]=[CH:20][N:21]=1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: Nc1ncco1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(Nc1ncco1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in tetrahydrofuran (10 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min. 1,3-Oxazol-2-amine (54.7 mg, 0.65 mmol) was then added and the reaction mixture was refluxed overnight. The reaction mixture was concentrated. Water (100 ml) was added to the residue followed by extraction with ethyl acetate (3×50 ml). The combined organic phase was washed with saturated brine (25 ml), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether:ethyl acetate=2:1) followed by Prep-HPLC (Gilson GX-281; Shimazu 15 μm; 250*19 mm; A: 10 mmol NH4HCO3/water, B: CH3CN; 0-9 min, 70-80%; 9-9.3 min, 80-95%; 9.3-13 min, 95% CH3CN; RT: 8.0 min) to yield the title compound as a white solid. 15 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:22]=[CH:21][NH:20][N:19]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([NH:17][C:18]2[N:22]=[CH:21][NH:20][N:19]=2)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1nc[nH]n1
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
161 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 51 mg of 3-amino-1,2,4-triazole were added to 1.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 153 mg of 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 29) represented by the formula:
Reaction SMILES: [ClH:1].C(O[C:7]([N:9](C)[CH2:10][CH2:11][N:12]([CH3:30])[S:13]([C:16]1[CH:25]=[CH:24][C:23]2[NH:22][C:21](=[O:26])[C:20]3[NH:27][CH:28]=[CH:29][C:19]=3[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=O)(C)(C)C.[CH2:32]([C:35]([O-:37])=[O:36])[CH2:33][CH3:34]>C(OCC)C.O1CCCC1>[CH3:30][N:12]([CH2:11][CH2:10][NH:9][CH3:7])[S:13]([C:16]1[CH:25]=[CH:24][C:23]2[NH:22][C:21](=[O:26])[C:20]3[NH:27][CH:28]=[CH:29][C:19]=3[C:18]=2[CH:17]=1)(=[O:14])=[O:15].[ClH:1].[CH2:32]([C:35]([OH:37])=[O:36])[CH2:33][CH3:34]
Reactant: CCCC(=O)[O-]
Reactant: CN(CCN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)O
Product: CNCCN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
2 mL (4 mmol) of a 2M solution of hydrochloric acid in diethyl ether is added to a solution of 50 mg (0.1 mmol) of 8-{[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-methyl-sulfamoyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate dissolved in 5 mL of anhydrous tetrahydrofuran. The solution is stirred at room temperature for 3 days then the solid that forms is filtered, and triturated in diisopropyl ether to give 26 mg (60%) of 8-[methyl-(2-methylamino-ethyl)-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate hydrochloride in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.C(OCC)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: c1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-Methyl-2-butenoic acid (1, 5.10 g, 50.9 mmol) and AlCl3 (20.4 g, 153 mmol) were placed in a one-neck round-bottomed flask. Benzene (50 mL) was added, which produced vigorous bubbling. Upon completion of the bubbling, a capped condenser (i.e. closed system) was attached, the reaction mixture was stirred and placed in an oil bath at 65° C. The pressure in the system was occasionally released. The progress of the reaction was followed by following the loss of starting material by GC. If the reaction was not complete within 1 h, a small quantity of AlCl3 was added and stirring was continued. To the solution was added diethyl ether and the mixture was cooled to 0° C. Slowly conc. HCl and some water were added until all the solid dissolved and the pH was less than 2. The aqueous layer was extracted with diethyl ether three times. The organic layer was concentrated to 150 mL and then was extracted with a saturated sodium hydrogen carbonate solution six times. The combined aqueous layer were acidified with conc. HCl until the pH was less than 2. The acidic aqueous layer was extracted with diethyl ether three times and the accumulated organic layer was dried with magnesium sulfate. The solution was filtered and the diethyl ether was removed in vacuo producing a white solid (8.51 g, 47.7 mmol) in 94% yield, which did not need further purification. mp 55-56° C. 1H-NMR (400 MHz, CDCl3) 10.45 (bs, 1H, CO2H), 7.38 (d, 2H, J=7.2 Hz, H-11 and H-7), 7.32 (t, 2H, J=7.2 Hz, H-10 and H-8), 7.21 (t, 2H, J=7.2 Hz, H-9), 2.65 (s, 2H, H-2), 1.47 (s, 6H, H-5 and H-4); Mass spectrum (EI) 178 (23, M.+), 119 (100, [C9H11]+). For pioneering work to form 2 see: F. J. Eijkman (1908) Chem. Kentr. II, p. 110; or A. Hoffman (1929) J. Am. Chem. Soc. 51:2542.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][O:31]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@H:40]1[CH2:45][CH2:44][CH2:43][C@@H:42]([CH3:46])[N:41]1[C:47]1[N:51]2[CH:52]=[C:53]([O:56][C@H:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C@@H:60]([NH2:67])[CH2:59][CH2:58]3)[CH:54]=[CH:55][C:50]2=[N:49][N:48]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:94]1CCOC[CH2:95]1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:38][C:95]([NH:67][C@@H:60]2[C:61]3[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:57]([O:56][C:53]3[CH:54]=[CH:55][C:50]4[N:51]([C:47]([N:41]5[C@H:40]([CH3:39])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:46])=[N:48][N:49]=4)[CH:52]=3)[CH2:58][CH2:59]2)=[O:94])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:20])[CH3:21])[CH:25]([CH3:27])[CH3:26])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1OCCOC1CCCCO1)(C(C)C)C(C)C
Reactant: C1COCCO1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCO)(C(C)C)C(C)C
Temperature: 45 °C
Yield: 40 %

Procedure:
A solution of Intermediate 55e (710 mg, 2.17 mmol), Intermediate C (385 mg, 2.17 mmol) and DIPEA (250 μL, 3.25 mmol) in 1,4-dioxane (10 mL) was stirred at 60° C. overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a gum (1.25 g, quantitative) that was used without further purification in the next step. TLC [DCM/MeOH (9:1) Rf=0.4]. A solution of the above product (1.25 g, 1.30 mmol) in MeOH (30 mL) was treated with pyridinium p-toluenesulfonate (978 mg, 3.90 mmol) and the resulting mixture was heated at 45° C. overnight. The volatiles were removed under reduced pressure and the residue was taken up in DCM (80 mL) and washed with water (20 mL). The organic phase was separated using a phase separating cartridge and the organic layer was evaporated in vacuo. The product was purified by FCC, eluting with 0-10% MeOH in DCM, to give the title compound (430 mg, 40%). LCMS (Method 3): Rt 5.41 min, m/z 879,880 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH:17]1[CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])N=3)[N:22]=[CH:21][C:20]=2[O:19][CH2:18]1.[CH:33](N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH:17]2[CH2:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:33]=4)[N:22]=[CH:21][C:20]=3[O:19][CH2:18]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc3c(c2n1)CC(CBr)CO3
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Temperature: 80 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (301 mg, 1.46 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthrene (500 mg, 1.46 mmol, 1.0 eq) in N,N-dimethylformamide (15 mL), followed by N,N-diisopropylethylamine (281 μL, 1.61 mmol, 1.1 eq). After 24 hours stirring at 80° C., solvent is removed and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-yl-carbamic acid tert-butyl ester as a brown viscous oil (544 mg, 74% yield).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:10][CH:8]1[CH2:7][NH:6][CH2:5][C:4]2[CH:3]=[CH:2][O:1][C:9]1=2
Reactant: Fc1ccccc1Br
Reactant: OC1CNCc2ccoc21
Product: Brc1ccccc1OC1CNCc2ccoc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4]O)#[N:2].N1C=CC=CC=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4][Br:20])#[N:2]
Reactant: BrP(Br)Br
Reactant: N#CC(CO)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(CBr)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 24 g (0.11 mol) 2-cyano-2-(4-bromophenyl)-ethanol and 4.5 g (0.055 mol) pyridine in 100 ml CH2Cl2 are slowly added, at -5° to 0°, 12 g (0.044 mol) PBr3. The mixture is stirred for 3 hours at room temperature, thereafter for 2 hours at 40°, allowed to cool off, then poured into 500 ml ice water and extracted with CH2Cl2. The extract is washed with water, dried and evaporated. The resulting residue is chromatographed over a silica gel column with hexane/diethylether 6:4. The glassy residue obtained after evaporation is worked up in toluene and thereafter ether to give the title compound in the form of a yellow powder, m.p. 171° (decomposing).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:11][CH:12]([OH:22])[CH:13]([OH:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C(OCC)C>[CH2:14]([CH:13]1[CH:12]([CH2:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:22][C:1](=[O:2])[O:21]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cl
Reactant: OC(Cc1ccccc1)C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1OC(Cc2ccccc2)C(Cc2ccccc2)O1
Reaction time: 0.25 h

Procedure:
Phosgene gas was slowly bubbled into a solution of 1,4-diphenyl-2,3-butanediol (Neher (1963) Hel. Chim. Acta. 46:1083) (96 mg, 0.4 mmole) and triethylamine (0.16 ml, 1 mmole) in anhydrous ethyl ether (75 ml). After 15 min, the phosgene addition was stopped, the solution filtered, and the solvent removed in vacuo (20° C./60 mm Hg) leaving a crystalline residue, which was flash chromatographed (CH2Cl2 eluent) affording 4,5-dibenzyl-1,3-dioxolan-2-one as a colorless, crystalline compound (98 mg, 94%): mp 155°-156° C.; IR (KBr) 3020, 1783, 1200, 1166, 1150, 1092, 1067, 1030, 765, 755, 703 cm-1 ; 'H NMR (CDCl3) 2.88(m, 4H), 4.55(t, J=3 Hz, 2H), 7.33(m, 10H); MS (70 eV) C17H16O3 calcd. 268.3235 obsd. 268.1096.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH3:8].[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 185.8 %

Procedure:
To a solution of 4-fluoronitrobenzene (5 g, 35.4 mmol) in THF (50 mL), 1-isopropylpiperazine (4.54 g, 35.4 mmol) and K2CO3 (7.35 g, 53.2 mmol) are added. The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude compound is purified by silica gel column chromatography using 99:1 and 98:2 DCM:NH3 (7M in MeOH) to give the title compound (8.2 g, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C([N:21]([CH2:24][CH3:25])CC)C.Cl.N[C@H:28]1CC[O:30][CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:21][CH:24]3[CH2:25][CH2:28][CH2:29][O:30]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: N[C@H]1CCOC1
Reactant: CCN(CC)CC
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Agent: Cl
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NC3CCCO3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt (14 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:35])([O:26][C:27]([NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][C@@H:30]([NH:29][C:27]([O:26][C:24]([CH3:35])([CH3:25])[CH3:23])=[O:28])[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O

Procedure:
When the above reaction was run using 15.6 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 10.2 g (55 mmol) of (R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 10.1 g (0.1 mol) triethylamine and 100 ml of acetonitrile, the yield of the title compound was 23.8 g.
Reaction SMILES: C[C:2]1[CH:8]=[C:7](C)[CH:6]=[C:5](C)[C:3]=1[NH2:4].[Li]CCCC.[Br:16][CH2:17][CH2:18][CH2:19]Br>O1CCOCC1.CCCCCC.CC(C)=O.CCCCCC>[Br:16][CH2:17][CH2:18][CH2:19][NH:4][C:3]1[CH:2]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: BrCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 22 %

Procedure:
To a stirred ice-cold solution of 2,4,6-trimethylaniline (13.5 g, 100 mmol) in dioxane (50 mL) under argon was added 1.2 equivalents of 1.6 M n-BuLi in hexane drop-wise. The brown mixture was allowed to warm up to room temperature during 1 h. At the end 50 mL (approx. 5 equiv.) of 1,3-dibromopropane was added in one lot and stirred for 42 h. Precipitated LiBr was filtered and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (300 mL) and water (3×100 mL). The organic layer was dried (Na2SO4) and evaporated to give the crude product whose purity by LC-mS analysis was 61%. Silica gel chromatography of the crude product with acetone/hexane (1:9) as eluent gave pure bromopropyl aniline (3.3 g) and an impure fraction which upon crystallization from ethyl acetate hexane gave an additional 2.4 g. (22% yield). LC/MS: tR=1.2 min; [M+H]=256, 258 (bromine pattern), 1H NMR (CD3OD) δ 7.07 (2 H, s), 3.59 (2 H, t, Jvic=6.4 Hz), 3.51 (2 H, t, Jvic=8.1 Hz), 2.46 (6 H, s), 2.45-2.38 (2 H, m), 2.30 (3 H, s) 2-Bromo-5-methyl-3-[3-(2,4,6-trimethyl-phenylamino)-propyl]-3H-imidazole-4-carboxylic Acid Ethyl Ester, scheme 7: GG)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[C:28]([CH3:35])=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[C:28]([CH3:35])=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(F)cccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1c(F)cccc1-n1nccc1-c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=431.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[C:17]([O-])(=[O:19])[CH3:18].[Na+]>Cl.O>[C:10]([NH:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:17](=[O:19])[CH3:18])(=[O:12])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(Cl)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
28.4 g (0.2 mol) of 4-chloro-1,2-phenylenediamine were dissolved in 130 ml of 3 molar hydrochloric acid and diluted with 300 ml of water. 51 g (0.5 mol) of acetic anhydride were added dropwise and then the reaction mixture was stirred at room temperature for 30 minutes, 41 g (0.6 mol) of sodium acetate were added, and the mixture was extracted with ethyl acetate. Workup of the organic phase resulted in a yield of 21% of the product.