Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([CH2:25][CH2:26][CH3:27])[CH3:24]>>[CH3:24][CH:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCCC(C)Br
Product: CCCC(C)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 127 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-bromopentane and conditions outlined in procedure V. M.p.=109-111° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.9 (s, 2H), 2.8-2.6 (m, 5H), 2.1 (d, 2H), 1.85 (q, 2H), 1.55 (m, 1H), 1.4-1.15 (m, 3H), 1.0 (t, 3H), 0.9 (t, 3H); LCMS: 372 [M+H].
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17](S(C)(=O)=O)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Reactant: C1COCCN1
Product: Cc1ccccc1-c1nc(N2CCOCC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Yield: 91.9 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 21; 88.0 mg) was reacted with morpholine (15.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido(4,5-b][1,5]diazocine (81.8 mg, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[F:9][C:10]1[CH:15]=[C:14]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1ncc(Br)cn1
Product: Nc1ncc(-c2ccc(-c3ccccc3-c3cnc(N)nc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 838 using 5-bromopyrimidin-2-amine in Step A and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C20H15FN6, 358.13; m/z found, 359.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.57 (s, 2H), 8.16 (d, J=2.0, 2H), 7.57-7.45 (m, 5H), 7.14 (t, J=10.3, 2H).
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14]=[C:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>ClCCl>[OH:3][PH:1]([CH2:14][CH:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:2]
Reactant: O=[PH2][O-]
Reactant: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 99.8 %

Procedure:
A mixture of ammonium phosphinate (162.6 g, 1.96 mol) and 1,1,1,3,3,3-hexamethyldisilazane (316 g, 1.96 mol) was heated to 105° C. for 2 hours. The reaction mixture was cooled in an ice bath and di-tert-butyl 2-methylenepentane-1,5-dioate (251 g, 0.979 mol) dissolved in dichloromethane (1000 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then quenched with distilled water (500 ml) and the organic layer was retained. The aqueous layer was washed a second time with dichloromethane and the combined organic layers were dried over magnesium sulfate. Then the solvent was removed under reduced pressure leaving a slightly yellow oil (315 g, 100%) This product was found to be of sufficient purity for use in the next reaction. 1H NMR (CDCl3) δ 1.4 (m, 18H), 1.9 (m, 3H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 6.5 & 7.9 (d, 1H, the P-H), 11.0 (s, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:18]1[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=1[OH:20])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCC1=O
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1=C(O)C(=O)CCC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (101 mL, 161 mmol) was added to a stirred solution of diisopropylamine (22.96 mL) in methyl-THF (200 mL) at −10° C. The resulting solution was stirred at −10° C. for 15 mins. 1,2-cyclohexanedione (8.6 g) was added to the reaction mixture as a solution in methyl-THF (28 mL). During the addition the internal temperature of the reaction was maintained between −15° C. and −5° C. by modulation of delivery rate. The resulting dark orange/brown solution was stirred at −10° C. for a further 15 mins. The reaction mixture was then cooled to −78° C. and ethyl bromoacetate (12.76 mL) was added dropwise via syringe. Further ethyl bromoacetate (0.8 mL) was added, no further evolution of heat was observed therefore the reaction was left to stir at −60 to −70° C. (internal temp) for 1 hour 15 minutes. The reaction mixture was quenched at −78° C. with 0.5 M HCl (400 ml), allowed to warm to RT and extracted with diethyl ether (200 ml). The organic layer was washed with water (300 mL) and saturated brine. The crude reaction mixture was purified by flash column chromatography (100 g, silica, ethyl acetate/cyclohexane, 0-50%) to give the title compound (7.1 g). LC/MS MH+ 199, Rt 1.78 mins (5 min system).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])([O-])=O.[K+].[K+].[Br:44][CH2:45][CH2:46]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:44][CH2:45][CH2:46][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:6]2[CH:7]=[C:8]3[C:16](=[C:4]([C:1](=[O:3])[NH2:2])[CH:5]=2)[NH:15][C:14]2[CH:13]=[C:12]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[CH:11]=[CH:10][C:9]3=2)=[CH:31][C:32]=1[Cl:37]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(O)c(Cl)c4)cc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCBr)c(Cl)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 155.6 %

Procedure:
A 100 ml round bottom flask was loaded with tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-hydroxyphenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate (estimated purity ˜50%, 365 mg, ˜0.35 mmol, Example 409B), K2CO3 (1.12 g, 8.10 mmol), DMF (20 ml) and 1,2-dibromoethane (0.64 ml, 7.4 mmol) and stirred at room temperature for 17 hours. The reaction mixture was poured into a separating funnel that was loaded with 500 ml water+citric acid (0.5 M solution in water) (60 ml, 30 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 342 mg tert-butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate, which was used without further purification. Estimated purity (from LCMS) ˜55%. MS (ESI) m/e+=627/629/631, m/e−=625/627/629 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[NH:13][C:12]([CH:16]([F:18])[F:17])=[N:11]2)=[C:4]([F:19])[CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH3:20])[C:12]([CH:16]([F:17])[F:18])=[N:11]2)=[C:4]([F:19])[CH:3]=1
Reactant: COc1cc(-n2nc(C(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A stirred mixture of 2.0 g (0.0067 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one and 2.1 g (0.015 mole) of potassium carbonate in 50 mL of acetone was heated at reflux for 30 minutes forming a thick slurry. Iodomethane (4.3 g, 0.03 mole) was added in one portion to the refluxing reaction mixture. After complete addition the mixture was stirred at reflux for 45 minutes. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure leaving a solid residue. This residue was partitioned between water and methylene chloride. The two phase mixture was filtered through a celite pad. The organic phase was removed and was washed in succession with four portions of an aqueous 10% sodium hydroxide solution, and one portion each of an aqueous 10% hydrochloric acid solution, a saturated aqueous sodium carbonate solution, and water. After washing, the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.6 g of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one. A portion of this material was recrystallized from ethanol and water to provide the product as a light tan solid (mp 127°-129° C.), Compound 22.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][CH:14]=2)[N:3]=1.[CH2:28]([P:31](C1C=C(C=CC=1)N)([CH2:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH3:30].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:26]([P:31]([CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH3:30])=[O:32])[CH:27]=2)[N:3]=1
Reactant: CCCP(=O)(CCC)c1cccc(N)c1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 3-(dipropylphosphoryl) aniline (Compound 168C) and 2,4-dichloro-5-trifluoromethylpyrimidine. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.00 (td, J=7.26, 0.88 Hz, 6H), 1.47-1.58 (m, 2H), 1.64-1.77 (m, 2H), 1.82-1.94 (m, 2H), 1.97-2.10 (m, 2H), 7.33-7.40 (m, 1H), 7.51 (td, J=7.83, 3.28 Hz, 1H), 8.00 (d, J=8.34 Hz, 1H), 8.08 (d, J=12.13 Hz, 1H), 8.60 (s, 1H). MS (ES+): m/z=405.97 (100) [MH+]. HPLC: tR=3.47 min (polar—5 min).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:13])(=O)=O>C1(C)C=CC=CC=1>[Cl:13][CH:3]([C:2](=[O:1])[CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 104 g (0.8 mol) of methyl 3-oxopentanoate (available from Wacker Chemical) in 500 ml of toluene was cooled to 0 to 5° C., and 108 g (0.8 mol) of sulfuryl chloride was added thereto dropwise, followed by stirring at room temperature overnight. Toluene was removed by evaporation to give 131.6 g (0.8 mol; yield: 100%) of the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)ncn1
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 93.5 %

Procedure:
Crude 4-hydroxy-6-phenylpyrimidine (3.65 g) was heated to reflux with phosphoryl chloride (40 ml) for 90 minutes. The reaction mixture was cooled and then concentrated under reduced pressure to afford a brown solid. The brown solid was partitioned between water and ether and the combined ether extracts washed with brine, dried and evaporated to give 4-chloro-6-phenylpyrimidine (2.18 g, 93.5% pure by GC analysis) as a yellow solid which was used directly in the next stage.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([Br:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared as in EXAMPLE 1, substituting 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid in Part C. HPLC: RT=10.39 min. MS (ESI−): mass calcd. for C23H17Br2FN4O5S2, 672.34; m/z found, 671 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.42 (s, 1H), 8.37 (d, J=7.1, 1H), 8.22 (d, J=8.8, 1H), 7.88 (s, 1H), 7.75-7.71 (m, 1H), 7.27-7.25 (m, 1H), 7.11 (q, J=8.4, 2H), 7.09-6.94 (m, 2H), 6.56 (d, J=7.0, 1H), 4.94 (q, J=5.8, 1H), 3.82 (s, 3H), 3.25-3.11 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH2:40])=[NH:39])=[CH:33][CH:32]=2)[CH:28]=[CH:29][N:30]=1>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:11]3[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[N:40]=[C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:27]4[CH:28]=[CH:29][N:30]=[C:26]4[CH3:25])=[CH:32][CH:33]=3)[N:39]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCC2CCCCC2)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1nccn1-c1ccc(Nc2nc(CCC3CCCCC3)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Yield: 45 %

Procedure:
tert-Butyl 4-(2-cyclohexyl ethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (393 mg, 45%) was synthesised from tert-Butyl 3-(3-cyclohexylpropanoyl)-4-oxopiperidine-1-carboxylate and 1(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 517.1 (M+H)+
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:7](F)[N:6]=1.CN>C(Cl)(Cl)Cl>[F:12][C:8]1[C:7]([NH:3][CH3:1])=[N:6][C:5]([F:4])=[C:10]([F:11])[CH:9]=1
Reactant: Fc1cc(F)c(F)nc1F
Reactant: CC#N
Agent: CN
Solvent: ClC(Cl)Cl
Product: CNc1nc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 10 ml of acetonitrile were added 4.5 g of 2,3,5,6-tetrafluoropyridine and 10 ml of methylamine (10% aqueous solution), and the mixture was stirred at 50° C. for 2 hours. To the solution was added 50 ml of chloroform, and the mixture was washed four times with 250 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a pale brown crude oil.
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[NH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].[F:19][C:20]([F:26])([F:25])[C:21](OC)=O>CO>[NH2:14][C:13]1[N:12]=[C:10]([NH:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:11]=[C:21]([C:20]([F:26])([F:25])[F:19])[N:15]=1
Reactant: N=C(N)NC(=N)NCc1ccccc1
Reactant: COC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc(NCc2ccccc2)nc(C(F)(F)F)n1
Temperature: 0 °C

Procedure:
To benzylbiguanide hydrochloride (11.3 g., 0.05 mole) in methanol (270 ml.) is added powdered sodium methoxide (5.4 g., 0.1 mole) followed by methyl trifluoroacetate (6.4 g., 0.05 mole) dropwise with stirring. The solution is stirred at room temperature for 64 hours, then poured into ice-water (500 ml.) and a white solid precipitated and is filtered off, m.p. 183°-185°C. Crystallization from acetonitrile affords colorless cubic crystals, m.p. 184°-185°C. Yield 8 g. (60%)
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:20])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>O>[O:25]1[CH2:24][CH:23]1[CH2:21][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:20])[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11]2)=[CH:6][CH:5]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12

Procedure:
To a solution of 82.2 g (2.06 mol) of sodium hydroxide in 585 ml of water were added 3.7 liters of issopropanol and then 490 g (2.06 mol) of 7-hydroxyflavone. To the above mixture were then added 1645 ml (20.5 mol) of epichlorohydrin and the mixture was heated at 70° for 2 hr with stirring. The hot reaction mixture was filtered to remove a solid dimeric by-product. The filtrate was concentrated under reduced pressure (water aspirator) at 50° to 60°. The semisolid residue was treated with 4.4 liters of refluxing isopropanol and more of the dimer from the hot mixture. The clear filtrate on cooling yielded a solid. This was filtered, washed with 600 ml of isopropanol and air dried; yield 434.3 g (72%) of a tan-colored product, m.p. 123°-130° (a pure sample of the title compound melts at 133°-135°.)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[NH2:11][C:12]1[NH:13][C:14](=O)[C:15]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1>C(#N)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:15]=2[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of 1,2,4-triazole (1.4 g, 20 mmol) and phosphorus oxychloride (1.4 mL, 15 mmol) in dry acetonitrile (40 mL) was adder to a stirred suspension of 2-amino-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (1 g, 5 mmol) and N-N-di-isopropyl-ethyl-amine (DIEA; 4.4 ml, 25 mmol) in dry acetonitrile (30 ml). The mixture was stirred at room temperature for 24 hours. 2 molar equivalents of 1,2,4-triazole (0.7 g, 10 mmol), 1.5 equivalent of phosphorus oxychloride (0.7 ml, 7.5 mmol) and 2.5 equivalents of DIEA (2.2 ml, 12.5 mmol) were added to the mixture. After stirring at room temperature for 48 hours, the same amount of the above reagents was added again. The reaction mixture was stirred for 7 full days and the yellow precipitate was filtered off, washed successively with acetonitrile, DCM and ether. The solid was dried under vacuum, providing the pure title compound as a yellow solid (667 mg, yield 53%) which was characterised as follows: MS (m/z) 248.8 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][CH:14]([NH2:17])[CH2:15][NH2:16])=[CH:10][CH:9]=[CH:8]2)[CH3:2].[C:18](O)(=O)C.C(N)=N>CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][CH:14]1[CH2:15][NH:16][CH:18]=[N:17]1)=[CH:10][CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cccc2cccc(CC(N)CN)c12
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: CCc1cccc2cccc(CC3CNC=N3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A solution of 3-(8-ethyl-naphthalen-1-yl)-propane-1,2-diamine (60 mg) in EtOH (6 ml) was treated at r.t. under an argon atmosphere with formamidine acetate (30 mg). The reaction mixture was stirred at r.t. overnight, then concentrated. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2→CH2Cl2/MeOH 9:1) to give (RS)-4-(8-ethyl-naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole (38 mg) as light yellow gum. MS (ISP): 239.3 ((M+H)+).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:23]2[CH2:22][CH2:21][CH:20]([CH:8]3[CH2:7][C:6]4[C:11](=[CH:12][CH:13]=[C:14]([CH3:15])[C:5]=4[O:4][CH:1]([CH3:3])[CH3:2])[CH:10]([CH2:16][NH:17][CH:18]=[O:19])[O:9]3)[CH2:25][CH2:24]2)=[CH:29][CH:28]=1
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(c1OC(C)C)CC(C1CCN(Cc3ccc(F)cc3)CC1)OC2CNC=O

Procedure:
Stir a suspension of N-((1R,3S)-5-Isopropoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (1.0 mmol) with 4-fluorobenzaldehyde (3.0 mmol) and sodium triacetoxyborohydride (3.0 mmol) in dichloromethane (5 mL) at room temperature overnight. Apply the reaction mixture directly to a 5 g SCX column and elute and concentrate the appropriate fractions to obtain N-[3-[1-(4-fluoro-benzyl)-piperidin-4-yl]-5-isopropoxy-6-methyl-isochroman-1-ylmethyl]-formamide. Use the compound directly for the next step.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].Br[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:34](=[O:35])[O:33]1.Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:34](=[O:35])[O:33]3)=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) was dissolved in dimethylformamide (1 ml). 3-Bromophthalide (69 mg) was added to the solution. After stirring for one hour at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml) and saturated aqueous NaCl (10 ml×2), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml) and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals well filtered, and dried under reduced pressure to give the title compound (45 mg).