Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[NH2:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1

Procedure:
A homogeneous solution of 0.175 of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 3 mL of 1N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Addition of 2 mL of acetic acid followed by centrifugation gave 0.125 g (86) of the title compound, which can be alternatively named as 5,10-dideazafolic acid, as a microcrystalline colorless solid, mp >200° C.; NMR (TFA-d1) delta 2.3-2.7 (m, 2H), 2.7-3.0 (m, 2H), 3.25 (s, 5H), 4.9-5.25 (m, 1H), 7.35, 7.85 (AB q, 4H, J=9 Hz), 8.50 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: COC1C=CC(C([C@@:22]2([OH:61])[C@@H:26]([CH2:27][O:28][C:29]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(C3C=CC(OC)=CC=3)[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[O:25][C@@H:24]([N:52]3[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]3=[O:54])[CH2:23]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(#N)C.O>[CH2:47]([CH2:46][C:29]([O:61][C@@H:22]1[C@@H:26]([CH2:27][O:28][C:29]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[O:25][C@@H:24]([N:52]2[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]2=[O:54])[CH2:23]1)=[O:28])[CH2:48][CH2:49][CH3:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)C(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CC#N
Product: CCCCCC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
To a stirred solution of 40.0 g of thymidine (0.165 mol) in 500 mL of pyridine was added 56.0 g of dimethoxytrityl chloride (0.165 mol), and the mixture was stirred at room temperature for 3 hours. To the mixture, 16.7 g of sodium hydrogen carbonate was added. The resulting mixture was stirred at room temperature for 30 min and evaporated under a reduced pressure. To the residue was added 500 mL of n-butyl acetate. To the stirred mixture was added 500 mL of water and the mixture was stirred for 10 min. Then, the organic layer was separated and washed with 500 mL of water. The organic layer was evaporated under a reduced pressure. The residue was recrystallized from 900 mL of n-butyl acetate to give a crystalline product, which was then collected by filtration. The crystalline product was dried in vacuo at 50° C. to a constant weight to give 74.6 g of the product. The product was analyzed by high performance chromatography (HPLC) with a reverse-phase octadecyl silica gel column using a mixture of acetonitrile/water (75/25) as an eluent and using a UV detector (254 nm), indicating a purity of 99.6%. A major impurity was 3′,5′-O-bis(4,4′-dimethoxytrityl)thymidine with an HPLC peak area of 0.3%. An yield was 75%.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:12]([NH:14][CH:15]1[C:39](=[O:40])[N:17]2[C:18]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:19]([OH:22])[CH2:20][S:21][C@H:16]12)=[O:13]>CN(C)C=O>[CH:12]([NH:14][CH:15]1[C:39](=[O:40])[N:17]2[C:18]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:19]([O:22][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Mesyl chloride (0.66 ml) and potassium carbonate (1.38 g) were added to a solution of benzhydryl 7-formamido-3-hydroxy-3-cephem-4-carboxylate (2.05 g) in N,N-dimethylformamide (6 ml) at -30° C. The mixture was stirred at -30° C. for 30 minutes. Mesyl chloride (0.4 ml) was added to the mixture. The reaction mixture was stirred at -30° C. for 20 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in a small amount of ethyl acetate and the mixture was subjected to column chromatography on silica gel and eluted with a mixture of benzene and ethyl acetate (1:1). The eluent was evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-mesyloxy-3-cephem-4-carboxylate (0.85 g).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([Cl:15])[C:9]([Cl:14])=[C:10]([Cl:13])[C:11]([Cl:12])=[C:4]2[C:3]1=[O:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][N:2]1[C:3](=[O:16])[C:4]2=[C:11]([Cl:12])[C:10]([Cl:13])=[C:9]([Cl:14])[C:8]([Cl:15])=[C:5]2[C:6]1=[O:7])(=[O:20])=[O:19]
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON1C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C1=O
Yield: 87 %

Procedure:
N-Methanesulfonyloxytetrachlorophthalimide was prepared by the following procedure. To a flask equipped with a stirrer and addition funnel were added N-hydroxytetrachlorophthalimide (9.00 g, 0.030 mol), methanesulfonyl chloride (3.60 g, 0.032 mol), and 200 mL of methylene chloride. The mixture was cooled in ice and a solution of triethylamine (5.0 mL, 0.036 mol) in 25 mL of methylene chloride was added slowly. Upon completion of this addition the reaction mixture was diluted with 200 mL of methylene chloride and washed successively with water (250 mL), 5% aqueous sodium bicarbonate (250 mL), and water (250 mL). The organic layer which contained a substantial amount of precipitated product was evaporated, and the resulting solid was dried by addition of toluene and evaporation to give 9.89 g (87.0%) of pale yellow crystalline N-methanesulfonyloxytetrachlorophthalimide: mp 240°-241°; uv (CH3CN) 240 (51,400), 329 (2736), 340 nm (2937); ir (KBr) 3040 (w), 3020 (w), 2940 (w), 1800 (m), 1700 (vs), 1375 (s), 1330 (m), 1310 (m), 1180 (s), 1120 (m), 1030 (s), 965 (m), 790 (m), 725 (s); nmr (CDCl3) 3.53 (s); mass spectrum 376.8472 (calcd for C9H3NO5Cl4S: 376.8783). Anal. Calcd for C9H3NO5Cl4S: C, 28.52; H, 0.80; N, 3.70; O, 21.11; Cl, 37.42; S, 8.46. Found: C, 28.52, 28.94, 28.92; H, 0.80, 1.07, 1.05; N, 3.70, 3.84, 3.82; Cl, 37.42, 37.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH3:31][N:32]1[CH2:35][C:34]2([CH2:38][NH:37][CH2:36]2)[CH2:33]1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:37]2[CH2:38][C:34]3([CH2:35][N:32]([CH3:31])[CH2:33]3)[CH2:36]2)[N:8]=1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: CN1CC2(CNC2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4(CN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 26.2 %

Procedure:
In THF (15 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (120 mg, 0.27 mmol) and 2-methyl-2,6-diazaspiro[3.3]heptane (45 mg, 0.40 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.81 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol/triethylamine=10/1/0.008) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid (35 mg, 26% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Cl)[N:11]=[C:10]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Cl)[N:9]=1)=[O:6].CN(C=O)C.CC(C)([O-])C.[K+]>C(Cl)Cl>[N:7]1([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[N:11]=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[N:9]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCCCl)Nc1nc(NC(=O)CCCCl)nc(NC(=O)CCCCl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1c1nc(N2CCCC2=O)nc(N2CCCC2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
440 mg of N,N',N"-tris(4-chlorobutyryl)melamine was placed in a flask equipped with a magnetic stirring bar, a reflux condenser, an argon inlet and a rubber septum. To the flask was added 6ml DMF followed by 450 mg potassium tert-butoxide, while stirring the reaction mixture at room temperature for about 30 minutes. It was then diluted with CH2Cl2 and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was then purified by column chromatography (silica gel) to give 180 mg of pure 2,4,6-tris(pyrrolidin-2-on-1-yl)-1,3,5-triazine.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>C1COCC1.C(Cl)Cl>[Cl:26][C:5]1[CH:6]=[C:7]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])[C:2]([C:32]([C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:42])=[N:3][CH:4]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.6 ml (1.2 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of a solution of phthalic anhydride (148 mg, 1.0 mmol) in 1 ml of DCM. The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (70% ethyl acetate in hexane) to afford 80 mg of title compound as an off white solid. MS: (M+H)/z=564.0, (M-32)/z=532.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:13]=[C:14]1[CH2:19][C:18](=O)[CH2:17][N:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:15]1>C(O)(=O)C>[Br:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:18]1[CH2:17][N:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:15][C:14](=[O:13])[CH:19]=1
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2=CC(=O)CN(C(=O)OCc3ccccc3)C2)c1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in 10 mL of acetic acid at 25° C., under nitrogen. The mixture was stirred for 8 hours at 70° C. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 0.13 g (51%) of benzyl 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate as a tan foam. 1H NMR (CDCl3-d1) δ 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 459.0.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc2ccccc2o1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzofuran-2-sulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (0.4 mg). MS m/z 369 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[OH:21])[CH3:12].Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[C:15]([CH2:19][CH3:20])[C:14]([OH:21])=[C:13]([CH2:11][CH3:12])[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: CCc1cccc(CC)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: CCc1cc(Cc2cnc(N)nc2N)cc(CC)c1O

Procedure:
2,4-Diamino-5-hydroxymethylpyrimidine (1.4 g.), prepared as in Example 1, and 2,6-diethylphenol (1.6 g.) in toluene-4-sulphonic acid (10 g.) containing conc. hydrochloric acid (3 ml.) were heated on the steam-bath for 6 hours. The solution was cooled, diluted with ether and the ether decanted. The residue was treated with a soln. of sodium hydrogen carbonate and the solid filtered off. Recrystallisation from aqueous ethanol gave colourless needles of 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine, m.p. 200°-202° C.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]=2O)=[NH:13])[CH:8]=[CH:9][CH:10]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]([C:14]2[O:15][C:16]3[C:23]([NH:24][C:32](=[O:34])[CH3:33])=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=2)=[NH:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a dichloromethane solution of 42 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 μl of pyridine and 200 μl of acetic anhydride. The resulted solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluted with 5-10% methanol/dichloromethane to give 43 mg of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide in 99% yield.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7]2.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([C:13]2[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7]3)[CH2:30][CH2:29]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=CCc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(CCc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Reaction time: 18 h

Procedure:
A slurry of the 3-{5-[2-oxoethyl]-1H-indol-2-yl}quinolin-2(1H)-one (10-2, 75 mg, 0.25 mmol, 1 equiv) and 1-(methylsulfonyl)piperazine (163 mg, 1.0 mmol, 4 equiv) in 1,2-dichloroethane(100 mL) was treated with acetic acid (0.67 mg, 1.12 mmol, 4.5 equiv) and sodium triacetoxyborohydride (156 mg, 0.75 mmol, 3 equiv) and the reaction was stirred under ambient conditions for 18 hours. The reaction was concentrated and the residue was partitioned between EtOAc and sat. NaHCO3 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on a silica column. Elution with EtOAc to 5% NH3-EtOH/EtOAc gave 3-(5-{2-[4-(methyl-sulfonyl)piperazin-1-yl]ethyl}-1H-indol-2-yl)quinolin-2(1H)-one (10-3) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.2 (s, 1H), 11.4 (s, 1H), 8.52 (s, 1H), 7.72 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1 H), 7.42 (d, J=8 Hz, 1 H), 7.38 (m, 2 H), 7.25 (m, 2H), 6.99 (d, J=8 Hz, 1H), 3.11 (m, 4 H), 3.87 (s, 3H), 2.81 (br t, J=8 Hz, 2 H), 2.61 (br t, J=8 Hz, 2H), 2.56 (m, 4 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[OH:6].[H][H]>O.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[OH:7]
Reactant: C=CCCP(=O)(O)CCCN
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CCCCP(=O)(O)CCCN

Procedure:
A solution of 1 g of 3-aminopropyl(but-3-enyl)phosphinic acid in 25 ml of water is treated with 0.1 g of 5% palladium on charcoal and hydrogenated at room temperature until hydrogen uptake ceases. The catalyst is removed by filtration of the reaction mixture through celite and the filtrate evaporated to dryness, to afford 3-aminopropyl(butyl)phosphinic acid, m.p. 231°-234° (dec.) 31 -NMR (D2O): δ +44.6 ppm.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[O:8]([NH2:10])[CH3:9].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:36]4[C:31](=[CH:32][C:33]([O:43][CH3:44])=[C:34]([O:37][CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:35]=4)[CH:30]=[CH:29]3)=[O:27])=[CH:22][CH:21]=2)=[C:16]([CH3:45])[CH:15]=1)(=O)[CH3:12]>CO>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][O:37][C:34]1[CH:35]=[C:36]2[C:31]([CH:30]=[CH:29][N:28]2[C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:11](=[N:10][O:8][CH3:9])[CH3:12])=[CH:15][C:16]=3[CH3:45])=[CH:25][CH:24]=2)=[O:27])=[CH:32][C:33]=1[O:43][CH3:44]
Reactant: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C(C)=O)cc4C)cc3)c2cc1OCCN(C)C
Reactant: CON
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1ccc(-c2ccc(C(=O)n3ccc4cc(OC)c(OCCN(C)C)cc43)cc2)c(C)c1
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
Potassium t-butoxide (0.11 g, 1.0 mmole) was added to methanol (10 ml) with stirring under argon and after 20 minutes at room temp. the solution was treated with methoxylamine hydrochloride (0.11 g, 1.3 mmole). The resulting mixture was stirred at room temp. for 20 minutes, then treated with a solution of 1-(4'-acetyl-2'-methylbiphenyl-4-carbonyl)-6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (E5, 0.30 g, 0.63 mmole) in methanol (10 ml). The mixture was stirred for 18 h at room temp. followed by heating under reflux for 3 h, then concentrated in vacuo. The residue was treated with 10% Na2 CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 0-5% methanol/dichloromethane to afford the title compound (0.20 g, 63%), mp 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[F:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:27][C:26]([CH2:25][CH2:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:31]=[CH:32][C:33]([F:34])=[C:12]([F:11])[CH:13]=3)[CH2:17][CH2:18]2)=[O:30])=[N:28][N:29]=1
Reactant: NNC(=O)CCC(=O)NC1CCN(Cc2ccc(F)c(F)c2)CC1
Reactant: S=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(CCc1nnc(Nc2ccccc2Cl)o1)NC1CCN(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isothiocyanato-benzene (0.125 g) and N-[1-(3,4-difluorobenzyl)-piperidin-4-yl]-3-hydrazinocarbonyl-propionamide (0.20 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.35 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-cyclohexylcarbodiimide N-methyl polystyrene HL (0.682 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.094 g, m.pt. 162-163° C., MS [M+H]+ (APCI+) 476/8).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10]([C:12]1[C:13]([C:18]([F:21])([F:20])[F:19])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10]([C:12]1[C:13]([C:18]([F:19])([F:21])[F:20])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: C=C(C)c1sccc1NC(=O)c1cn(C)nc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)c1sccc1NC(=O)c1cn(C)nc1C(F)(F)F
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 10 ml of methanol, 1 g of the compound prepared in Example 6 (Compound No. 1.71) was dissolved, 0.2 g of 5% Pd/C was added, and catalytic reduction was carried out at the room temperature for 8 hours under atmospheric pressure. After finishing the reaction, the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The resulting oily material was sludged with hexane to obtain 0.8 g of the desired product as a crystal. The yield was 79%.