Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Li]CCCC.[C:16](=[O:18])=[O:17].O>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C=O
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Yield: 20.4 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (0.48 g, 2.43 mmol) in 1 ml of toluene at −78° C. was added 1 ml of 2.6M n-BuLi in toluene followed by quenching with dry ice (0.5 g, 12.5 mmol). The reaction mixture was warmed to room temperature, then taken into water and extracted with ethyl acetate (2×15 ml). The water layer was acidified to pH 1-2 by addition of concentrated aqueous hydrochloric acid and extracted with ethyl acetate (3×15 ml). The organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated to give 4-cyano-2-methylbenzoic acid (0.08 g, 20% yield). 1H-NMR (400 MHz, DMSO-d6): 13.10 (br s, 1H), 7.92 (d, 1H), 7.84 (m, 1H), 7.76 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:16].Cl.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:36].[ClH:16].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])[CH2:28][CH2:27]2)=[CH:31][CH:32]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCCCCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 116.3 %

Procedure:
The procedure described in Example 29 was followed using n-dodecyl isocyanate (2.11 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole) methylene chloride (100 ml), and triethylamine (3.03 g; 30 mmole). Recrystallization from water provided the title compound (3.21 g; 58% yield) as colorless crystals, m.p. 215°-222° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]=[C:1]([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=Nc1ccccc1Cl)c1ccccc1

Procedure:
A solution of acetophenone (130 ml), 2-chloroaniline (130 ml) and benzene (200 ml) was refluxed in the presence of molecular sieve with continuous removal of water. o-Chloro-N-(α-methyl benzylidene) aniline (XXI) was obtained by fractional distillation. XXI had a boiling point of 111° C. at 0.1 millimeter.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].ClCCl.[Cl:24][C:25]([Cl:29])([Cl:28])[S:26]Cl>O>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:25]([Cl:29])([Cl:28])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Temperature: 0 °C
Reaction time: 0.37 h

Procedure:
To an ice cold solution of 2.40 g of sodium hydroxide in 70 ml of water is added 14.46 g (0.06 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil. Then 100 ml of dichloromethane is added. To this mixture, at 5°, is added 6.6 ml (0.06 mol) of trichloromethane sulfenyl chloride in two volumes of dichloromethane. The mixture is stirred approximately 22 min at 5°. Then the phases are separated and the organic phase is washed with ice cold water. The dichloromethane solution is dried over magnesium sulfate, filtered and stripped. The residue is triturated with ether/pentane, filtered and dried to obtain the crude product, which is then purified by crystallization to yield 5-cyano-1-(2,6-dimethylphenyl)-3-trichloromethanesulfenyluracil, m.p. 223°-225.5°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl.[NH+]1C=CC=CC=1>O>[CH:12]1[C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][C:14]=2[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1cccc2c1sc1ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1ccccc1-c1cccc2c1sc1ccccc12
Temperature: 60 °C
Yield: 62.9 %

Procedure:
4-(2-Methoxyphenyl)dibenzo[b,d]thiophene (6.6 g, 23 mmol) and pyridinium hydrochloride (27 g, 230 mmol) were mixed together, placed in the 100 ml round bottom flask and heated to reflux for 45 min. Reaction mixture was cooled to 60° C., diluted with 100 ml water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica (eluent hexane/ethyl acetate 5/1), providing 4.00 g of 2-(dibenzo[b, d]thiophen-4-yl)phenol as clear solidified oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].[C:14](O)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:14]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
After 18 hours methyl-α-D-glucopyranoside (64 g, 0.33 mol, prepared according to example 6), dodecanoic acid (90 g, 0.45 mol) and 6 g lipase were added. After additional 22 hours the enzyme was removed by filtration and the product was worked up by short path distillation according to example 1, yielding a crude product containing 84% 6-O-dodecanoyl-D-glucopyranoside 9% methyl-D-glucoside and 7% diesters Part of the product was purified by chromatography and the identity of the title compound (being a ca 1:1 mixture of the anomers) was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)=[CH:24][N:23]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nnc(-c2ccc(Cl)nc2)o1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nnc(-c2ccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)nc2)o1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (90 mg, 0.31 mmol) and 2-chloro-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (60 mg, 0.31 mmol) as starting materials.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[Br:24][C:12]1[CH:11]=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:4]([OH:3])=[O:23])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(OC)cc1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)CC(O)(C(=O)O)C(F)(F)F)cc1Br

Procedure:
From 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid ethyl ester by bromation with N-bromosuccinimide in dimethylformamide at 0° C. and subsequent saponification. Melting point 94-96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:21]3[N:20]=[C:19]([NH2:18])[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
Compound 47 (0.05 g, 0.21 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.05 g, 0.19 mmol) in tert-butanol (5 mL) at 25° C. The mixture was subsequently stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.07 g (83%) of the title compound: TLC (Rf =0.35; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.15 (s, 1H), 8.75 (d, 2H), 7.73 (s, 1H), 7.69 (d, 2H, J=8.7), 7.51 (s, 1H), 6.66 (d, 2H, J=8.4), 6.57 (d, 1H, J=7.3), 4.52 (d, 2H, J=13.2), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (m, 1H), 3.73 (s, 3H), 3.43 (m, 2H), 2.05 (m, 2H), 1.44 (m, 2H); 13C NMR (CDCl3) δ 166.3, 161.4, 155.2, 151.7, 151.0, 146.7, 136.0, 131.0, 115.8, 111.3, 104.9, 101.6, 99.2, 56.2, 56.0, 51.2, 47.9, 43.4, 31.0; Anal. (C23H27N5O4 ·1HCl) C, H, N.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[C:7]([CH3:9])=[CH2:8])[CH:2]1[O:4][CH2:3]1.C[O:12]C1C=CC(O)=CC=1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[C:6]([O:5][CH2:1][CH:2]([CH2:3][OH:12])[OH:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OCC(O)CO
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a two phase mixture of 86 g (0.6 mol) of comercial glycidylmethacrylate containing 200 ppm of MEHQ and 500 ml of water is added 2 ml of concentrated sulfuric acid at ambient temperature. After stirring approximately 18 hours, the mixture appeared as a clear homogenous solution. To the resultant solution is added sufficient sodium sulfate to cause separation of an oil. The 2 phase mixture is extracted sequentially with 5 portions of 150 ml each of chloroform and the combined chloroform extracts are dried over solid sodium sulfate. After filtering the solid sodium sulfate, the solvent is removed by evaporation to give 77 g (80%) of glycerol mono-methacrylate as a clear colorless oil. The monomer can be used without further purification or can be further purified by chromatography to separate trace amounts of glycerol di-methacrylate.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([Br:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([OH:28])[C:5]=1[OH:29].[C:30](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[C:5]([O:29][CH3:30])=[C:6]([OH:28])[CH:7]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([Br:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(O)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 27.5 %

Procedure:
Iodomethane (0.074 mL, 1.2 mmol) was added dropwise to a rt, stirred light suspension of 3-bromo-5-(6-bromo-benzo [b]naphtho [2,3 -d]thiophen-11 -yl)-benzene-1, 2-diol (0.30 g, 0.60 mmol), potassium carbonate (0.083 g, 0.6 mmol) in DMF (1.5 mL) over a period of five minutes. After the mixture was stirred at ambient temperature for 1.5 h., the reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (80 mL) and aqueous mixture was extracted with methylene chloride (120 mL). The organic extract was washed with water and dried with brine. Silica gel (5 mL) was added. Solvent was removed and the adsorbate was flash chromatographed (eluents:petroleum ether:methylene chloride 7:3 to 1:1 and then petroleum ether: ethyl acetate 7:3) to provide the title compound as a white solid (85 mg, 29%): mp 233-234° C.: NMR (CDCl3); δ8.35 (ddd, J=8, 1, 1 Hz, 1 H), 7.82 (ddd, J=8, 1, 1 Hz, 1 H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.65 (dd, J=8, 1, Hz, 1 H), 7.48 (ddd, J=8, 7, 1 Hz, 1 H), 7.43 (ddd, J=8, 7, 1 Hz, 1 H), 7.17 (ddd, J=8, 7, 1 Hz, 1 H), 7.15 (d, J=2 Hz, 1 H), 7.00 (d, J=2 Hz, 1 H), 6.87 (ddd, J=8, 1, 1 Hz, 1 H), 5.93 (s, 1 H), 4.14 (s, 3); MS (EI): [M+], 2 bromine isotope pattern, 512; Anal. Calc. for C23H14Br2O2S: C, 53.72, H, 2.74, N, 0.00. Found: C, 53.85, H, 2.98, N, 0.02.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Temperature: 25 °C
Yield: 38 %

Procedure:
Methyl 5-[2-(pyrrolidin-1-yl)ethylcarbamoyl]-thiophene-2-carboxylate (56 mg, 0.2 mmol) in ethanol (2.0 mL) was refluxed with heating with hydrazine monohydrate (0.10 mL) for 10 hours and allowed to cool to room temperature, and the precipitated solid was collected by filtration, washed with water and dried to give 21 mg of the desired product (yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:22]=[C:21]([Cl:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18](=O)[O:17][N:16]=2)=[CH:11][CH:10]=1.P(Cl)(Cl)([Cl:34])=O>N1C=CC=CC=1>[Cl:34][C:18]1[O:17][N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:21]([Cl:31])=[CH:22][C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:29])[Cl:30])=[CH:24][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[N:19]=1
Reactant: O=c1[nH]c(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3noc(Cl)n3)cc2)c(Cl)c1

Procedure:
90 mg of 3-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one, 14 mg of pyridine and 0.2 ml of phosphorus oxychloride are stirred for 14 hours at 130° C. The reaction mixture is poured onto ice-water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCCCN1CCCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carbonyl chloride (8.88 g, 49 mmol) in THF (100 mL) was added at 0° C. 4-pyrrolidin-1-yl-butylamine (7.0 g, 49 mmol). The reaction was stirred for 18 h at RT. The mixture was diluted with EtOAc, washed several time with aqueous 6 N NaOH and then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using a gradient CH2Cl2/MeOH/NH4OH (100%, 0%, 0% to 90%, 10%, 1%). The pure fractions were combined and the solvents removed under vacuum. The title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12]C[C:10]=13)=[CH:6][CH:5]=[N:4]2.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:3]2[N:4]=[CH:5][CH:6]=[C:7]2[N:8]=[C:9]2[C:10]=1[CH2:12][CH2:13][CH2:14][CH2:15]2
Reactant: Clc1c2c(nc3ccnn13)CCCCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccnn13)CCCC2

Procedure:
Using the method described for the preparation of 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 7,8-tetrahydro-pyrazolo[5,1-b]quinazolin-9-ol and phosphorus oxychloride provided the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[O:19])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1

Procedure:
To a suspension of 24.78 g (165 mmol) of benzylurea and 25 ml (165 mmol) of diethyl malonate in 84 ml of methanol, 40.2 ml (165 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 32.12 g (89.2%, white crystal) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]1[NH:29][C:30]([CH3:33])=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:26][CH2:27][C:28]1[NH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: Cc1ccc(CN)[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(C(=O)NCc2ccc(C)[nH]2)cc1OC

Procedure:
18.1 g (0.1 mol) of 3,4-dimethoxybenzoic acid are reacted with 17.8 g (0.11 mol) of carbonyldiimidazole and 11.0 g (0.1 mol) of 2-aminomethyl-5-methyl-pyrrole (compare Example 11), as described in Example 15.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]2[C@H:26]([CH3:27])[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])=[O:21])=[CH:14][CH:13]=1.[C:35]([O:39][C:40](=[O:43])[CH2:41]Br)([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[C:35]([O:39][C:40](=[O:43])[CH2:41][C@H:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[C:20]([N:22]1[C@H:26]([CH3:27])[C@H:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:24][C:23]1=[O:34])=[O:21])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
NaHMDS (1.0M, 17 mL, 17 mmol) was added to a stirred solution of (4R,5S)-3-[3-(4-Chlorophenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one (4.8 g, 14 mmol) in THF (200 mL) at −78° C. under N2. Stirred at −78° C. for 45 minutes and then Bromo-acetic acid tert-butyl ester (2.5 mL, 17 mmol) was added dropwise over 10 minutes. The solution was allowed to warm to −20° C. over 4 hours and then quenched with saturated aqueous NH4Cl. The product was extracted into EtOAc (2×300 mL), dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica (20% EtOAc/hexanes) to give (3S)-3-(4-Chlorobenzyl)-4-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-4-oxo-butyric acid tert-butyl ester (5.1 g, 80%.) 1H NMR (CDCl3, 400 MHz) δ 7.44-7.21 (9H, m), 5.45 (1H, d, J 7.3 Hz), 4.68-4.62 (1H, m), 4.51-4.42 (1H, m), 3.01 (1H, dd, J 13.0 and 6.2 Hz), 2.78 (1H, dd, J 16.7 and 10.6 Hz), 2.63 (1H, dd, J 13.2 and 9.0 Hz), 2.32 (1H, dd, J 6.7 and 4.3 Hz), 1.38 (9H, s), 0.89 (3H, d, J 6.6 Hz.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[CH:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Br)cc1NCCO
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (I-19, Aldrich, Wis.; 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0.23 mol, 2.0 eq.) in n-butanol (300 mL) was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were removed by filtration to give I-20 as a yellow powder (29 g, 98%). MS (ESI): m/z 262 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:2].[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1([CH:7]([CH3:8])[CH3:9])[O:14][CH2:13][CH2:12][O:10]1)[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C(C)C)OCCO1
Yield: 82.1 %

Procedure:
To a solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (79 g, 0.5 mol) and ethane-1,2-diol (62 g, 1 mol) in toluene (1600 mL) was added TsOH (1.9 g, 0.1 mol). The mixture was refluxed till the reaction was over. The mixture was concentrated in vacuum to give the crude (2-isopropyl-[1,3]dioxolan-2-yl)-acetic acid ethyl ester (83 g, crude), which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:11][C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[I:8].O.NN>C(O)C>[NH2:15][CH2:14][C@@H:12]1[O:11][C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of (5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (1021, 23.3 g, 50.0 mmol) in ethanol (EtOH, 150 mL) was treated with hydrazine monohydrate (12.52 g, 12.1 mL, 250 mmol, 5.0 equiv) at 25° C., and the resulting reaction mixture was warmed up to reflux for 2 h. White precipitates were formed while the reaction mixture was refluxed. When TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being quenched with H2O (100 mL). The white precipitates were totally dissolved when water was introduced into the reaction mixture and a homogeneous solution was generated. The aqueous solution was then extracted with CH2Cl2 (3×200 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 16.0 g, 16.8 g theoretical, 95.2%) as white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1022: C10H10FIN2O2, LCMS (EI) m/e 337 (M++H).
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]([CH3:16])([CH3:15])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(OCC)C>[CH2:1]=[N:3][C:4]([CH3:16])([CH3:15])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: C=O
Reactant: CC(C)(N)C(=O)OCc1ccccc1
Solvent: CCOCC
Product: C=NC(C)(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
37% Aqueous formaldehyde solution (17.3 g) was added over 10 minutes to a stirred solution of benzyl 2-amino-2-methylpropanoate (28.0 g) in diethyl ether at ambient temperature. The two phase mixture was stirred for 21/2 hours then diluted with diethyl ether and washed with brine. The ethereal solution was dried (magnesium sulphate) and solvent evaporated under reduced pressure to give benzyl 2-(N-methyleneamino)-2-methylpropanoate (29.4 g) in equilibrium with its trimer 1,3,5-tri(1-benzyloxycarbonyl-1-methylethyl)hexahydrotriazine as a colourless oil, IR (liquid film) 2980(m), 1725(vs), 1250(m), 1135(vs).