Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31](O)=[O:32])=[CH:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:32])=[CH:22]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1c[nH]c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 290 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 140 mg indole-3-acetic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. 910 mg of a residue are obtained. The residue is purified by silica gel flash chromatography. 180 mg of the title compound are obtained after drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:18]3[N:17]([C:18]4[CH2:19][CH2:20][CH2:21][N:17]=4)[CH2:21][CH2:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1S2

Procedure:
Reaction of 2-methoxyphenothiazine, 2-pyrrolidinone and phosphorus oxychloride in 1,2-dichloroethane according to the procedure of Example 1 affords 2-METHOXY-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 151°-153° C. (corr.), from isopropyl alcohol.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.C[C:6]([N:10]1CCOCC1)=[CH:7][CH2:8][CH3:9].[CH:16](Cl)(Cl)Cl>>[CH3:1][C:3]1[CH:4]=[CH:9][CH:8]=[C:7]([CH3:16])[C:6]=1[NH2:10]
Reactant: C=CC=O
Reactant: CCC=C(C)N1CCOCC1
Reactant: ClC(Cl)Cl
Product: Cc1cccc(C)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
14.0 g (0.25 mol) of acrolein is added dropwise at maximal temperature of 40° C. to a solution of 23.3 g (0.15 mol) of N-(2-penten-2-yl)-morpholine in 100 ml of abs. chloroform. The mixture is stirred for 15 hours at 25° C. and then for further 15 hours at 50° C. Thereafter the solvent is distilled off and the residue is transferred into an autoclave and, after addition of 400 ml concentrated aqueous ammonia and 10.0 g of paladium coal (5%) the whole is heated under a nitrogen pressure of 50 bar for 15 hours at 280° to 290° C. Subsequently the catalyst is separated by filtration and washed with ether. After separation of the etheral layer the filtrate is several times extracted with ether. The extracts are combined and dried over magnesium sulphate and the ether is distilled off. The residue (22 g) is distilled in vacuo. There is obtained 6.5 g (35% of theory) of 2,6-dimethylaniline, b.p. 15 : 94°-96° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](OC)[C:10]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:19])[C:10]=1[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COc1cccc(OCc2ccccc2)c1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: Cc1cccc(OCc2ccccc2)c1C=O
Reaction time: 1.75 h
Yield: 89.8 %

Procedure:
In a nitrogen stream, a solution of (2-benzyloxy-6-methoxyphenyl)-methanol (3.46 g, 15.16 mmol) and N-methylmorpholine N-oxide (NMO, 2.66 g, 22.73 mmol) in dichloromethane (10 mL) was cooled in a water bath and tetra-n-propyl-ammonium perruthenate (TPAP, 152 mg, 0.43 mmol) was added thereto. The reaction mixture was stirred at the same temperature for 1.75 hours, and then subjected to Celite filtration and the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (3.08 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[C:17](/[CH:21]=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[S:3]([CH2:6][CH:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:31])([F:30])[F:13])[CH:16]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Reactant: CN(C)S(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 676 mg (5.49 mmol) of N,N-dimethylmethanesulphonamide in 10 ml of THF was admixed slowly at −78° C. with 3.43 ml (5.49 mmol) of 1.6M n-butyllithium solution in hexane versetzt. After 30 min at −78° C., the colourless solution obtained was added to a solution, cooled to −78° C. beforehand, of 500 mg (1.83 mmol) of the compound from Example 11A in 10 ml of THF. The reaction mixture was stirred at −78° C. for 30 min more and then slowly warmed to RT. After 30 min it was cooled to −20° C. again and the reaction was halted by addition of 5 ml of 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate and then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC [Method 23]. The product fraction was freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 296 mg (41% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:8]2[C:7]([NH:6][CH2:5][C:4]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:3]=3[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])=[CH:12][CH:11]=[CH:10][N:9]2[C:13]=1[CH3:17]
Reactant: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 12 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
To an ice cooled solution of 8-(2-aminomethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.17 g, 0.58 mmol), pyridine (0.046 g, 0.58 mmol) in methylene chloride (8 ml) was added methyl chloroformate (0.055 g, 0.58 mmol) and the reaction mixture was stirred for 1.5 h. and the temperature was allowed to raise to 12° C. Methylene chloride was added and the solution was washed twice with water. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent. Recrystallization from diethyl ether gave 0.052 g (25%) of the title compound.
Reaction SMILES: CCN([C:6]1[CH:11]=CC(C([C:24]2[CH:29]=[C:28](S(O)(=O)=O)[CH:27]=CC=2S([O-])(=O)=O)C2C=CC(=[N+](CC)CC)C=C2)=[CH:8][CH:7]=1)CC.[Na+].CN1[CH2:45][CH2:44][N:43]([C:46](=[O:50])[C:47]([CH3:49])=C)CC1.[C:51]([O:55]CCOCC)(=[O:54])[CH:52]=[CH2:53]>>[OH:54][C:6]1[CH:11]=[CH:45][C:44]([NH:43][C:46](=[O:50])[CH:47]=[CH2:49])=[CH:8][CH:7]=1.[C:51]([O:55][CH2:27][CH2:28][CH2:29][CH3:24])(=[O:54])[CH:52]=[CH2:53]
Reactant: C=CC(=O)OCCOCC
Reactant: CCN(CC)c1ccc(C(c2cc(S(=O)(=O)O)ccc2S(=O)(=O)[O-])C2C=CC(=[N+](CC)CC)C=C2)cc1
Reactant: C=C(C)C(=O)N1CCN(C)CC1
Agent: [Na+]
Product: C=CC(=O)Nc1ccc(O)cc1
Product: C=CC(=O)OCCCC

Procedure:
(P-188): N-Methyl-N'-methacryloylpiperazine-2-ethoxyethyl acrylate copolymer (40/60)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[OH:20].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:20][C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:15][C:10]=2[N:9]=1
Reactant: Oc1ccc(C(F)(F)F)cc1N=Cc1ccncc1Cl
Solvent: CO
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Reaction time: 2.5 h
Yield: 19.9 %

Procedure:
To a mixture of 0.71 g of 2-(3-chloropyridin-4-yl)methylideneamino-4-(trifluoromethyl)phenol and 10 ml of methanol, 0.80 g of iodobenzene diacetate was added at room temperature and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. Organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.14 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 18”).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:12]C(=O)OC(C)(C)C)[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([OH:11])[CH3:10]
Reactant: CC(O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 19.3 g of tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate in 160 cm3 of dioxane and 67 cm3 of 6.5N hydrochloric dioxane is stirred at room temperature for 5 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A yellow oil is obtained, and is taken up in 50 cm3 of water and basified to a pH in the region of 10 with potassium carbonate. This mixture is extracted with 3 times 100 cm3 of ethyl acetate and the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 12.9 g of a 75%/25% mixture of the two diastereoisomers A and B of (3R)-3-amino-4-phenyl-2-butanol are obtained in the form of an orange-colored oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm). A mixture of diastereoisomers is observed: from 0.70 to 1.50 (broad unres. mult.: 2H); 1.08 (d, J=6 Hz: 3H); from 2.25 to 2.45 (mt: 1H); from 2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25 to 4.75 (unres. mult.: 1H); from 7.10 to 7.35 (mt: 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.BrC1C=CC=C2C=1C=C([C:27]([OH:29])=[O:28])C=C2.Cl[C:31]1N=C(C)C=C[C:32]=1[C:33](O)=O>>[N:12]1[N:11]([C:4]2[CH:1]=[CH:2][CH:10]=[C:9]3[C:5]=2[C:6]([C:27]([OH:29])=[O:28])=[CH:33][CH:32]=[CH:31]3)[N:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: O=C(O)c1ccc2cccc(Br)c2c1
Product: O=C(O)c1cccc2cccc(-n3nccn3)c12

Procedure:
The title compound was prepared in a manner analogous to Intermediate 47 substituting 8-bromo-2-napthoic acid for 2-chloro-6-methylnicotinic acid. The desired 8-[1,2,3]triazol-2-yl-naphthalene-1-carboxylic acid was obtained (474 mg, 16%). MS (ESI): mass calculated for C1H9N3O2, 239.20; m/z found 240.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.13 (t, J=9.0 Hz, 2H), 7.95-7.91 (m, 3H), 7.82 (dd, J=7.4, 1.0 Hz, 1H), 7.70 (dd, J=9.8, 5.8 Hz, 1H), 7.64-7.59 (m, 1H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.C(COC)OC.[CH3:16][Si:17]([CH3:27])([CH3:26])[O:18][CH2:19][CH2:20][C-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[K+]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH:4]1([Zr+2:9][C:21]2([CH2:20][CH2:19][O:18][Si:17]([CH3:16])([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25]2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: [Zr+3]C1C=CC=C1
Reactant: C[Si](C)(C)OCC[c-]1cccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C[Si](C)(C)OCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Reaction time: 12 h
Yield: 27 %

Procedure:
To a suspension of 3.52 g (10 mmol) of an adduct of cyclopentadienyl zirconium trichloride with dimethoxyethane in toluene, a suspension of 2.2 g (10 mmol) of potassium (2-trimethylsiloxy-ethyl)-cyclopentadienide in toluene is added. The addition is carried out at −78° C. An orange-brown suspension is immediately formed; it is maintained under stirring for 12 hours; then it is left settling and it is filtered. The obtained orange solution is concentrated up to 5 ml and hexane is added, so that a brown solid is obtained. (1.1 g, 2.7 mmol. Yield: 27%). 1H-NMR: 6.00 (t, 2H), 5.87 (s, 5H), 5.67 (t, 2H), 3.66 (t, 2H), 2.92 (t, 2H), 0.11 (s, 9H). Mass spectrum. M+-65: (343): 33%.
Reaction SMILES: [C:1]([CH2:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH2:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH:25][C:9](=[O:11])[C@@H:8]([CH2:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
A suspension of 3.0 g (12 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0.184.550) and 2.66 g (11 mmol) of L-histidine methyl ester dihydrochloride in 340 ml of dimethylformamide is treated at room temperature under a nitrogen atmosphere with 3.45 g (34 mmol) of triethylamine and 4.58 g (12 mmol) of HBTU. The reaction mixture is stirred at room temperature for 5 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 500 ml of ethyl acetate and washed in succession with 100 ml of water, three times with 100 ml of saturated sodium bicarbonate solution each time and 100 ml of saturated sodioum chloride solution. The organic phase is dried over sodium sulphate, evaporated under reduced pressure and the yellowish crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.1% ammonia. In this manner there are obtained 3.6 g of N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine methyl ester as a colourless foam, MS: 399 (M)+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH2:14][C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16].[CH3:29]I.Cl>O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH:14]([CH3:29])[C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)C(C)C(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.92 g, 0.098 mol, 60%) and tetrahydrofiran (100 mL) are placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, ice bath, addition funnel, internal thermometer and argon inlet. The contents of the flask are cooled to 0° C. 3,7-Dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate (15.28 g, 0.044 mol) dissolved in 50 mL of tetrahydrofuran is added dropwise to the flask over 30 min. During addition, the mixture evolves gas. After stirring for 1 h, methyl iodide (10.65 g, 0.075 mol) is added to the reaction mixture. Stirring continues for 2 h at 0° C. and then at room temperature for 18 h. The mixture is neutralized with 20% HCl and extracted with diethyl ether. The organic layers are washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by flash chromatography to yield the desired compound. Structure is confirmed my 1H and 13C NMR.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)[CH3:11].C(OC(ON=C(C#N)C(N)=O)=O)C.O>O1CCCC1>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1

Procedure:
To a solution of benzoic acid (1.22 g) and triethylamine (2.8 ml) in dry tetrahydrofuran (20 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.85 g) is added at room temperature while stirring, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is admixed with water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate, 1 N hydrochloric acid and water in order, dried and concentrated to give ethyl benzoate (1.3 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][OH:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH:7]=[C:6]([F:15])[C:3]=1[CH2:4][O:5][C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]1[CH2:32][CH3:33])=[O:30]
Reactant: OCc1c(F)cc(OCC2CC2)cc1Cl
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCC2CC2)cc1Cl
Yield: 95 %

Procedure:
This compound was prepared from 2-Chloro-4-cyclopropylmethoxy-6-fluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (580 mg; 95%); MS (ISP): 488.4 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].CN.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:38][CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1cccc(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 69.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added methylamine (2.0 M soln. in THF, 0.018 mL, 0.036 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (10 mg, 65%). LC-MS m/z 482 (M+H)+; 1H-NMR (MeOD) δ 2.16 (s, 6H), 2.38 (m, 2H), 2.96 (s, 3H), 3.22 (m, 2H), 4.45 (s, 2H), 7.16 (m, 2H), 7.50 (m, 1H), 7.64 (m, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.00 (s, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]N1C(=O)CCC1=O.ClC(Cl)CCl>>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2S1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCC(Cl)Cl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl

Procedure:
A solution of 500 mg. (1 mmol.) of p-nitrobenzyl 6β-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg. (1 mmol.) of N-chlorosuccinimide in 40 ml. of well dried 1,1,2-trichloroethane was refluxed for 90 minutes. The mixture was cooled, washed with water and brine, dried, and the solvent evaporated in vacuo. According to the nmr spectrum the title compound was obtained in nearly quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]([O:32][CH:33]=[CH:34][C:35](Cl)=[O:36])[CH2:29][CH2:30][CH3:31].O>C(OC(C)C)(C)C>[CH2:28]([O:32][CH:33]=[CH:34][C:35]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:36])[CH2:29][CH2:30][CH3:31]
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CCCCOC=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Yield: 98 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (1.8 g), diisopropyl ether (20 ml) and triethylamine (0.87 g) is added dropwise a solution of β-n-butoxyacrylic acid chloride (1.4 g) in diisopropyl ether (5 ml) with stirring and heating at 70° C. After completion of dropwise addition, the mixture is further stirred with heating at the same temperature for 0.5 hour. After cooling, water is added to the reaction mixture and the mixture is subjected to extraction with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give N-(β-n-butoxyacryloyl)-N-(1-benzyl-4-piperidinyl)aniline (2.6 g).