Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N:12]([CH3:14])[CH3:13])[C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[C:18]([S:22][C:23]([F:26])([F:25])[F:24])[C:17]([C:27]#[N:28])=[N:16]1.ClC[CH2:31][S:32][CH3:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:42]CCCCCC.C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([N:12]([CH3:13])[CH3:14])[C:3]=1[N:15]1[C:19]([N:20]([CH3:42])[CH2:21][CH2:31][S:32][CH3:33])=[C:18]([S:22][C:23]([F:24])([F:25])[F:26])[C:17]([C:27]#[N:28])=[N:16]1
Reactant: CNc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1N(C)C
Reactant: CSCCCl
Reactant: CCCCCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CSCCN(C)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1N(C)C

Procedure:
To a mixture of 1-(2-chloro-6-dimethylamino-4-trifluoromethylphenyl)-3-cyano-5-methylamino-4-trifluoromethylthiopyrazole (Compound number 4-01, 0.29 g, 0.7 mmol) in acetonitrile (6 ml) was added chloroethyl methylsulfide (87 mg, 0.8 mmol) and potassium phosphate (0.42 g, 2.0 mmol). The mixture was heated under reflux for 4 hours. After extractive workup (heptane-ethyl acetate, water) and reverse HPLC chromatography the title product was obtained (0.16 g), 1H-NMR: 1.99 (3H), 2.31 (2H), 2.69 (6H), 2.85 (3H), 3.18 (2H), 7.15 and 7.29; 19F-NMR: −44.7, −63.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.CCN(C(C)C)C(C)C.CN(C(O[N:43]1N=N[C:45]2[CH:46]=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([NH:43][CH2:44][CH2:45][CH3:46])=[O:19])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 5.7 %

Procedure:
To a solution of 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid (300 mg, 0.854 mmol), Hunig's base (0.597 mL, 3.42 mmol) and HATU (487 mg, 1.281 mmol) in tetrahydrofuran (10 mL) was added propan-1-amine (76 mg, 1.281 mmol). The reaction mixture was stirred at 20° C. for 2 hours. The solution was concentrated and purified by MDAP, to afford title compound (20 mg, 0.049 mmol, 5.69% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH:31](O)[CH2:32][CH3:33])=[CH:23]1.N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Br:20][CH2:33][CH2:32][CH2:31][C:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:22][CH:23]=1
Reactant: BrBr
Reactant: CCC(O)c1coc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrCCCc1coc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a 0° C. solution of triphenylphosphine (2.07 g, 7.90 mmol) in methylene chloride (20 mL) was added bromine (0.4 mL, 7.90 mmol) dropwise. To the resulting cloudy mixture was added a solution of 3-benzofuran-3-yl-propan-1-ol (1.16 g, 6.58 mmol) and pyridine (1.07 mL, 13.2 mmol) in methylene chloride (10 mL). The reaction was stirred at room temperature for 4 hours, then was diluted with diethyl ether (100 mL) and filtered. The ethereal solution was washed with 1 M aqueous potassium hydrogen sulfate (50 mL), then with saturated aqueous sodium bicarbonate (50 mL), and finally with brine (50 mL), then was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography on SiO2 (CH2Cl2) afforded 1.5 g (96%) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, J=7.8 Hz, 1 H), 7.47 (d, J=8.1 Hz, 1 H), 7.46 (s, 1 H), 7.7.22-7.35 (m, 2 H), 3.45 (t, J=6.4 Hz, 2 H), 2.87 (t, J=7.1 Hz, 2 H), 2.25 (quint, J=7.2 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22]O)[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[O:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH2:22][N:44]3[CH2:45][CH2:46][O:42][C:43]3=[O:47])[C:13]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1NCCO1
Reactant: CCOC(=O)CCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)CCCc1c(CN2CCOC2=O)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate (70.0 mg) in toluene (1 mL) was added tributylphosphine (0.098 mL), 1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. After stirring for 5 minutes, to the mixture was added 1,1′-(azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for 10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL) was added, and the mixture was filtered. The filtrate was evaporated. Preparative thin layer chromatography (ethyl acetate-hexane=1-1) afforded ethyl 4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate as an yellow gum (25.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[C:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:10]=1.CC1C=CC(S(O[CH2:40][P:41]([CH3:46])(=[O:45])[O:42][CH2:43][CH3:44])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:27][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:10]=1)[O:28][CH2:40][P:41]([CH3:46])(=[O:45])[O:42][CH2:43][CH3:44]
Reactant: COCOc1ccc(Cc2c(Cl)cc(O)cc2Cl)cc1Cc1ccc(F)cc1
Reactant: CCOP(C)(=O)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOP(C)(=O)COc1cc(Cl)c(Cc2ccc(O)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxymethoxybenzyl]phenol (0.08 gm, 0.19 mmol), acetonitrile (3 mL), ethyl [(4-methylphenyl)sulfonyloxymethyl]methylphosphinate (compound 74, 0.105 gm, 0.38 mmol), was added cesium carbonate (0.153 gm, 0.47 mmol). The reaction was heated at reflux for 2 hours, then stirred over night at r.t. The reaction was filter into 25 ml ethyl acetate, washed 1× with brine, dried over Na2SO4, filtered and concentrated. Ethyl [(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl]methylphosphinate was obtained by prep plate TLC using a 2 mm×20×20 cm SiO2 plate eluted with ethyl acetate. (0.06 gm, 60%); 1H NMR (300 MHz, DMSO-d6): δ 7.23 (s, 2H), 7.17 (m, 2H), 7.07 (t, J=8.7 Hz, 2H), 6.95 (m, 2H), 6.86 (m, 1H), 5.14 (s, 2H), 4.41 (m, 2H), 4.07 (s, 2H), 4.04 (m, 2H), 3.86 (s, 2H), 3.25 (s, 3H); 31p NMR (121.4 MHz, DMSO-d6): δ 46.13; TLC conditions: Uniplate silica gel, 250 microns; ethyl acetate; Rf=0.22.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:55]([NH:57][CH3:58])[CH3:56].C1C[O:62]CC1>>[CH:46]([OH:47])=[O:62].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:57]([CH2:55][CH3:56])[CH3:58])[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: CCNC
Product: CCN(C)CCOc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Yield: 50 %

Procedure:
A solution of Intermediate 154a (50.5 mg, 66 μmol) and N-ethylmethylamine (40 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 48 h in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give the title compound as a white solid (24 mg, 50%). LCMS (Method 5): Rt 3.69 min, m/z 720 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 0.94 (3H, t, J=7.2 Hz), 1.27 (9H, s), 1.46-1.55 (2H, m), 1.64-1.72 (2H, m), 1.76-2.09 (6H, m), 2.19 (3H, s), 2.41 (2H, quart, J=7.0 Hz), 2.68 (2H, t, J=4.7 Hz), 2.86-2.94 (1H, m), 3.12-3.19 (1H, m), 3.29-3.34 (1H, m, obscured by water peak), 4.08 (2H, t, J=6.1 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.4 Hz), 6.33 (1H, s), 6.94-6.98 (1H, m), 7.05-7.13 (3H, m), 7.19 (1H, dd, J=9.6 Hz, 2.2 Hz), 7.23-7.42 (5H, m), 7.64 (1H, d, J=10.2 Hz), 7.69 (1H, d, J=2.2 Hz), 8.13 (1H, s), 8.18 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S-:18].[Na+].C(OCC)C.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([S:18][CH3:17])[CH:12]=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 1-benzyloxy-3,5-dibromo-benzene (9.6 g, 28.1 mmol) in dry DMF (55 mL) was added sodium thiomethoxide (1.97 g, 28.1 mmol). The reaction mixture was then stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was poured into a mixture of diethyl ether (50 mL) and water (20 mL) along with intense stirring. The organic layer was separated and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes-acetone (5:0.2) as eluent to afford 3.68 g (42%) of title compound as an yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.41-7.26 (m, 5H); 6.96 (s, 1H); 6.90 (s, 1H); 6.80 (s, 1H); 5.05 (s, 2H); 2.46 (s, 3H).
Reaction SMILES: O[Li:2].O.C([O:6][C:7](=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.C1COCC1.O>CO>[C:12]([O:11][C:9]([CH2:8][C:7]([O-:16])=[O:6])=[O:10])([CH3:15])([CH3:13])[CH3:14].[Li+:2]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)[O-]
Product: [Li+]
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
LiOH.H2O (1.57 g, 37 mmol) was added to a solution of malonic acid tert-butyl ester ethyl ester (4.7 g, 25 mmol) in a mixture of methanol (23 mL), THF (47 mL) and H2O (14 mL). The reaction mixture was stirred for 1 hour at room temperature then concentrated to afford 4.0 g (96%) of lithium tert-butoxycarbonyl-acetate. 1H NMR: (DMSO-d6): δ 2.8 (s, 2H), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[N:11]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:15]=[C:14]([C:25]1[C:26]([CH3:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[N:13]=2>CN1CCCC1=O>[CH:34]1([CH2:33][N:11]2[C:10]([N:6]3[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]3)=[N:18][C:17]3[C:12]2=[N:13][C:14]([C:25]2[C:26]([CH3:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[N:15][C:16]=3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:35][CH2:36]1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3C[C@@H](C)N[C@@H](C)C3)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
cis-2,6-Dimethylpiperazine (114 mg, 1.0 mmol) and N-methylpyrrolidone (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (90 mg, 75%) as a light brown solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH2:10]([C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:5][CH2:6]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@H]1CC[C@H](CCBr)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCC[C@H]1CC[C@H](CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Product: [Br-]
Temperature: 5 °C
Reaction time: 60 h

Procedure:
A mixture of 13.0 g of 1-bromo-2-(trans-4-pentylcyclohexyl)ethane, 16.0 g of triphenylphosphine and 375 ml of xylene was heated to boiling for 60 hours. After cooling to 5° C., the precipitated product was filtered off under suction, washed with toluene and hexane and dried, there being obtained 15.0 g of 2-(trans-4-pentylcyclohexyl)ethyl-triphenylphosphonium bromide; m.p. 183°-185° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:27])[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>ClCCl>[CH2:20]([S:19][C:18]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:15]2=[O:27])=[CH:10][C:9]=1[O:8][C@@H:5]1[CH2:4][CH2:3][C@H:2]([NH:1][C:44](=[O:46])[CH3:45])[CH2:7][CH2:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](N)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
45 mg (0.073 mmol) of 6-(4-amino-cis-cyclohexyloxy)-7-benzylsulfanyl-2-(4-methoxybenzyl)-2H-iso-quinolin-1-one (127) were dissolved in 5 ml of dichloromethane and 14.8 mg (0.146 mmol) of triethylamine were added. At 0° C., 6.9 mg (0.088 mmol) of acetylchloride were added and the solution was stirred at room temperature. After 2 h, dichloromethane was added and the solution was washed with 2 N HCl and saturated sodium bicarbonate solution. After drying with magnesium sulfate and evaporation of the solvent, the title compound was isolated as crude product, which was used without further purification. Rt=1.53 min (Method C). Detected mass: 543.6 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[N:7]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:6]=1[CH3:27])=[O:4].[OH-].[Na+]>O1CCOCC1.O.C(OCC)C>[CH3:27][C:6]1[N:7]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:18])([F:20])[F:19])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccccc2OC(F)(F)F)n(C[C@@H]2CCCO2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: Cc1c(C(=O)O)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of 171 mg of 2-methyl-1-[(S)-1-(tetrahydro-furan-2-yl)methyl]-5-(2-trifluoromethoxy-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester in dioxane (4 ml) and water (4 ml) was added 1.3 ml of a 1N solution of sodium hydroxide. The reaction mixture was heated at reflux for 20 hours. After such time the reaction mixture was allowed to cool down to room temperature. The mixture was diluted with diethyl ether and extracted with 1N sodium hydroxide solution. Water phases were pooled, acidified with 2N solution of hydrochloride acid and extracted twice with diethyl ether. The organic phases were pooled, washed with brine and dried with MgSO4. Solvent was removed to give 154 mg of the title compound as brownish oil; MS (ISP) 368.0 (M−H).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1C=CC=CC=1.[OH-].[Na+]>CCOCC>[CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)COc1ccc(C=CC(=O)O)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A 500 mL, 1 neck, round-bottomed flask equipped with a magnetic stirrer and reflux condenser is charged with 4-(2-methylpropoxy)benzaldehyde (17.84 g, 0.100 mol, as from Example 2a), malonic acid (10.42 g, 0.100 mol), and 19 mL of pyridine. The mixture is heated with stirring in a 130° C. oil bath for 24 hours, then stirred at room temperature for 16 hours. The reaction mixture is then poured into a separatory funnel containing 300 mL of pH 12 aqueous sodium hydroxide and 300 mL of ether. The layers are separated and the aqueous phase washed with 150 mL of ether. The aqueous phase is then acidified with concentrated hydrochloric acid to bring the pH to 1 whereupon the powdery white acid precipitates out. The mixture is chilled in an ice/salt bath and the solid collected giving 5.89 g (0.027 mol, 27%) of product, m.p. 161°-164° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]1[CH2:14][CH2:13]OC1=O.COCCOCCO.C(=O)=O>>[CH3:9][NH:10][CH2:14][CH2:13][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCOC1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: COCCOCCO
Product: CNCCNc1ccccc1
Temperature: 170 °C
Reaction time: 17 h

Procedure:
A mixture of aniline hydrochloride (13.0 g, 0.10 mole), 3-methyl-2-oxazolidinone (11.0 g, 0.109 mole) and 35 ml of 2-(2-methoxyethoxy)ethanol was heated to 170° C. in an oil bath. The reaction mixture became homogenous and carbon dioxide evolution occurred on heating. After 17 hours, the reaction was allowed to cool to room temperature. After a workup procedure similar to that described in Example 1 and distillation at 105° C. to 110° C. (0.4 mm), an 81 percent distilled yield of the product was obtained as a clear liquid. Product confirmation was made by the use of spectra evidence.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:21](CC)CC>CN(C=O)C.Cl[Hg]Cl>[C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:21])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.2 %

Procedure:
To a solution of 205 (340 mg, 1.6 mmol), N,N'-bis-tert-butoxycarbonylthiourea (442 mg, 1.6 mmol, prepared according to literature procedure: Synthetic Commun.1993, 23, 1443.), and Et3N (292 mL, 3.36 mmol) in DMF (4 mL) at 0° C. was added HgCl2 (478 mg, 1.76 mmol) and the mixture was allowed to warm to rt overnight, stirring a total of 20 h. The crude product was isolated in the same manner as described in Example 201 and the was chromatographed on silica gel (5% ethyl acetate/dichloromethane) to afford bis-Boc-guanidine 206 (229 mg, 31%) as a pale orange solid: 1H NMR (300 MHz, CDCl3) d 1.49 (s, 9H), 1.54 and 1.56 (2s, 18H), 4.48 (br s, 2H, NOE observed for C-4 NH2 and C-3 H), 6.73 (d, 1H, J=8.4), 7.68 (dd, 1H, J=1.6, 8.4), 7.86 (s, 1H), 9.96 (s, 1H), 11.64 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].C[N:20]([CH:22]=O)C>C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:20][C:22]1[CH:4]=[CH:3][CH:2]=[CH:11][C:10]=1[CH2:9][CH2:8][CH3:7]
Reactant: CN(C)C=O
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Solvent: CC(=O)O
Product: CCCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(OC)cc12
Yield: 41 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.062 g, 0.23 mmol) 2-propylanilin (0.038 g, 0.28 mmol), 2-butanole (2 ml), DMF (2 ml) and acetic acid (8.2 μl) was heated over night at 100 C. After cooling, the solution was reduced by evaporation. The residue was dissolved in water (3 ml) and treated with aqueous ammonia. The solid product was filtered off washed with water air dried for 0.5 h, washed again with heptane and dried in a vacuum oven at 50 C. to give a yellow-brown solid, 35 mg (41%) of the title compound. APCI-LC/MS m/z 366.1 (MH+): 1H NMR (DMSO-d6) δ 10.95 (1H, s); 8.88 (1H, s); 8.28 (1H, br s); 7.62 (1H, br s); 7.29 (1H, m); 7.24 (1H, s); 7.05 (2H, m); 6.68 (1H, m); 6.63 (1H, s); 3.88 (3H, s); 3.21 (3H, s); 2.67 (2H, t); 1.65 (2H, m); 0.93 (3H, t).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.O>CC#N>[CH3:22][C:23]1([CH3:30])[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)CCC(N)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCC(Nc2ncnc3c([N+](=O)[O-])cccc23)CC1
Yield: 69.4 %

Procedure:
To a solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step-2, 150 mg, 0.72 mmol) in CH3CN (3 mL) were added K2CO3 (300 mg, 2.15 mmol) and 4,4-dimethylcyclohexanamine hydrochloride (352 mg, 2.15 mmol) and the reaction mixture was heated at reflux for 3 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.58-8.55 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.38-8.35 (d, J=7.2 Hz, 1H), 8.25-8.22 (d, J=7.8 Hz, 1H), 7.67-7.61 (t, J=7.8 Hz, 1H), 4.17 (m, 1H), 1.75-1.56 (m, 4H), 1.46-1.18 (m, 4H), 0.98 (s, 3H), 0.95 (s, 3H); MS [M+H]+: 301.20.