Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:3]=1
Reactant: Cc1cccc(C(=O)[C@@H](C)O)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: Cc1cccc([C@]2(O)OCC(C)(C)N[C@H]2C)c1
Yield: 65.4 %

Procedure:
Compound 4e was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-methylphenyl)-2-hydroxypropan-1-one (10e, 4.2 g, 0.026 mol), Proton sponge (6.5 g, 0.030 mol), triflic anhydride (4.60 mL, 282 mmol), and 2-amino-2-methyl-1-propanol (5.0 g, 0.056 mol) in acetonitrile (55 mL). After purification, 4.0 g (66%) of the free base 4e was isolated and converted to 3.6 g of the hemi-D-tartrate salt, which had 94% ee: mp 104-105° C.; [α]20D +11.9° (c 0.85, CH3OH); 1H NMR (methanol-d4) δ 7.43-7.38 (m, 2H), 7.28 (t, 1H, J=7.8 Hz), 7.21-7.18 (m, 1H), 4.33 (s, 1H), 4.20 (d, 1H, J=12.0 Hz), 3.52-3.45 (m, 2H), 2.38 (s, 3H), 1.61 (s, 3H), 1.36 (s, 3H), 1.06 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 179.0, 142.3, 139.4, 130.9, 129.5, 128.4, 125.0, 97.2, 75.3, 67.4, 55.2, 24.2, 21.9, 21.4, 14.4; LCMS (ESI) m/z 236.2 [(M-tartrate)+, M=C16H24NO5]; Anal. (C16H24NO5.0.75H2O) calcd: C, 59.33; H, 7.94; N, 4.32. found: C, 59.20; H, 7.88; N, 4.34.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:22])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C(C1C=CC(OC)=C(C=1)N)(C)(C)C.[C:36]([C:40]1[CH:41]=[CH:42][C:43]([O:69][CH3:70])=[C:44]([NH:46][C:47](NC2C3C(=CC=CC=3)C(OC3C=CN=C(C#N)N=3)=CC=2)=[O:48])[CH:45]=1)([CH3:39])([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:47]([NH:46][C:44]3[CH:45]=[C:40]([C:36]([CH3:37])([CH3:39])[CH3:38])[CH:41]=[CH:42][C:43]=3[O:69][CH3:70])=[O:48])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccc(Oc2ccc(N)c3ccccc23)n1
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(C#N)n2)c2ccccc12
Agent: COc1ccc(C(C)(C)C)cc1N
Product: COC(=O)c1nccc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)ccc3OC)c3ccccc23)n1

Procedure:
The title compound was prepared from the above amine and 5-tert-butyl-2-methoxyaniline by the procedure described for 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-cyano-pyrimidin-4-yloxy)-naphthalen-1-yl]-urea (Example 1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:20]([S-:22])#[N:21].[K+].BrBr>CC(O)=O>[CH3:1][N:2]([CH3:19])[CH:3]([CH2:17][CH3:18])[CH:4]([C:10]1[CH:16]=[CH:15][C:13]2[N:14]=[C:20]([NH2:21])[S:22][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: N#C[S-]
Reactant: CCC(C(c1ccc(N)cc1)n1ccnc1)N(C)C
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)aniline (600 mg, 2.32 mmol) and KSCN (508 mg, 5.22 mmol) in 15 mL AcOH was cooled to about 7° C. and treated with Br2 (125 μL, 2.43 mmol) in 2 mL AcOH added dropwise via syringe over 5 min. The reaction vessel was removed from the cooling bath and stirred at rt for 1 hr. The reaction was cooled in an ice bath and basified with 3N NaOH (100 mL) added portionwise over several minutes. This mixture was then extracted with DCM (4×75 mL). The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 6% MeOH (2N NH3)/DCM to give 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine as a yellow foam. MS ESI: m/z 316.16 [M+1+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].ClCCl.Cl[CH2:18]/[CH:19]=[CH:20]\[CH2:21]Cl>CCCCCC.C(OCC)(=O)C>[C:7]1([CH2:6][C@H:4]([N:5]2[CH2:21][CH:20]=[CH:19][CH2:18]2)[C:3]([O:2][CH3:1])=[O:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: ClC/C=C\CCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N1CC=CC1
Yield: 61.9 %

Procedure:
From L-phenylalanine methyl ester (365 mg, 2.04 mmol), dichloromethane (4 ml) and cis-1,4-dichloro-2-butene (71 mg, 0.58 mmol). Flash chromatography: silica gel, hexane:ethyl acetate (2:1) afforded the product (83 mg, 62%) as colourless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=1)(=[O:5])[CH3:4].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>O1CCCC1.CN(C)C=O>[C:3]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:10]([F:15])[CH:9]=1)(=[O:5])[CH3:4]
Reactant: COCCOCCl
Reactant: CC(=O)OCc1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(COC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
2.6 g (65.1 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 10 g (54.3 mmol) of (3-fluoro-4-hydroxy-phenyl)-methyl acetate diluted in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 45 minutes and then 6.8 ml (59.7 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 2 hours and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30. 9.7 g (65%) of [3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate is obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][C:8]#[N:9].[N:14]([Sn](CCCC)(CCCC)CCCC)=[N+:15]=[N-:16].C([Al](CC)CC)C>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][C:8]1[NH:16][N:15]=[N:14][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CNc1ccccc1OCCC#N
Agent: CC[Al](CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1ccccc1OCCc1nnn[nH]1
Temperature: 80 °C

Procedure:
To a solution of 3-(2-methylamino-phenoxy)-propionitrile (1.55 g, 8.8 mmol) and azidotributyltin (3.6 mL, 13.2 mmol) in toluene (30 mL) was added triethylaluminum (9.3 mL, 17.6 mmol, 1.9 M in toluene). The mixture was heated at 80° C. for 16 hrs. The mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The ethyl acetate layer was separated and removed. The resulting methyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine stayed in the aqueous solution and was used in the next step without purification. [M+H]+220.1; tR=0.388 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:8](=O)[CH3:9])=[N:6][CH:7]=1.[C:16](O)(=O)C.[CH:20]([NH2:22])=[NH:21]>COC(OC)N(C)C.C(O)C.C1(C)C=CC=CC=1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[N:6][C:5]=1[C:8]1[CH:9]=[CH:16][N:22]=[CH:20][N:21]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1ncc(N)nc1-c1ccco1
Reactant: N=CN
Agent: COC(OC)N(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Temperature: 115 °C
Reaction time: 9 h
Yield: 30 %

Procedure:
A solution of 1-[5-amino-3-(2-furyl)pyrazin-2-yl]ethanone (Preparation 4, 388 mg, 1.91 mmol) in N,N-dimethylformamide dimethyl acetal (1.3 mL) was heated to 100° C. After 9 h, the mixture was concentrated under reduced pressure to yield brown oil. Formamidine acetate (795 mg, 7.64 mmol) was added to this oily residue previously dissolved in ethanol (6.4 mL) and toluene (0.96 mL). Molecular sieves (4 Å) were added to the solution and the whole reaction mixture was heated to 115° C. in a sealed tube and stirred for 20 h. The crude reaction was filtered and concentrated to dryness. The residue was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by silica gel flash chromatography (100% ethyl acetate). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (137 mg, 30%).
Reaction SMILES: N[CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.S1C=CC=C1CC(Cl)=O.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:36]C1C(=O)N2C(C(O)=O)=C(COC(=O)N)CS[C@H]12)=[O:35]>>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:36][CH:7]1[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])=[C:5]([C:14]([OH:16])=[O:15])[N:4]2[C:17](=[O:18])[CH2:2][C@H:3]2[S:8]1)=[O:35]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C(Cl)Cc1cccs1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1NC(=O)Cc1cccs1

Procedure:
A third 1 μl portion of the 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid-containing solution, prepared as reported in Example 11, was treated as described in Example 11, except that the acyl halide was 2-thiopheneacetyl chloride, and the resulting product was 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. It exhibited an RCV value of 0.39.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]O)[N:10]=[C:4]2[CH:3]=1.S(Cl)([Cl:15])=O.O.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][Cl:15])[N:10]=[C:4]2[CH:3]=1
Reactant: OCc1cn2ccc(Br)cc2n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: ClCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 110 mg (0.48 mmol) of (7-bromoimidazo[1,2-a]pyrid-2yl)methanol, prepared according to the protocol described in step 8.2, in 8 mL of anhydrous dichloromethane, stirred at room temperature under an inert atmosphere, is added 0.03 mL (0.53 mmol) of thionyl chloride. The reaction mixture is stirred at room temperature for 4 hours, hydrolysed at 0° C. by successive addition of 3 mL of cold water and 5 mL of saturated aqueous NaHCO3 solution and then extracted with three times 10 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 80 mg of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].S(=O)(=O)(O)O.[O:10]=[C:11]1[O:17][C@H:16]([C@H:18]([CH2:20]O)[OH:19])[C:14]([OH:15])=[C:12]1[OH:13]>>[CH3:1][C:2]1([CH3:4])[O:19][CH:18]([CH:16]2[O:17][C:11](=[O:10])[C:12]([OH:13])=[C:14]2[OH:15])[CH2:20][O:3]1
Reactant: CC(C)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Yield: 115.4 %

Procedure:
With nitrogen substitution, 557.8 grams (9.6 moles) of acetone was cooled to −5 degrees C., 54.3 grams (0.2 moles) of 28% fuming sulfuric acid was dripped, and 176.1 grams (1.0 mole) of L-ascorbic acid was added. The mixture was then reacted at the temperature of the previous step for 17 hours, filtered and washed with cold acetone to obtain 249.5 grams of 5,6-O-isopropylidene-L-ascorbic acid (86.7% in purity) in the form of a wet cake.
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:18]([NH:22][C:23](=[NH:26])[O:24][CH3:25])([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:18]([NH:22][C:23](=[N:26][S:8](=[O:10])(=[O:9])[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:24][CH3:25])([O:20][CH3:21])=[O:19]
Reactant: O=S(=O)(Cl)NC1CCCCC1
Reactant: COC(=N)NC(=O)OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)NC(=NS(=O)(=O)NC1CCCCC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
59.6 parts of cyclohexylaminosulfonyl chloride and 26.9 parts of pyridine were introduced through two feed lines, into a stirred solution of 39.6 parts of N-carbomethoxy-O-methylisourea in 300 parts of ethyl acetate, at from 15° to 20° C. After having been stirred for 4 hours at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid and was then dried and concentrated under reduced pressure. This gave 79 parts of N-carbomethoxy-N'-cyclohexylsulfamyl-O-methylisourea, of nD25 =1.4970. After trituration with a small amount of ether, the compound crystallized, and these crystals melted at 84°-86° C. 15 parts of this product were dissolved in a mixture of 9 parts of 50% strength by weight sodium hydroxide solution and 20 parts of water and the reaction solution was stirred for 4 minutes at from 55° to 60° C. It was then cooled, extracted once with ether, and stirred into a mixture of 9.5 parts of concentrated hydrochloric acid and 10 parts of water. Filtering off the product, washing with water and drying gave 9 parts of 6-cyclohexyl-3-methoxy-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide, of melting point 173°-177° C. This constitutes active compound No. 3.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:24][CH2:25][OH:26]>CC#N.O.C([O-])(O)=O.[Na+]>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][OH:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: Ic1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCN1CCN(c2ccc(I)cc2)CC1
Temperature: 91 °C
Yield: 51.7 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (2.25 g, 7.8 mmol) and iPr2NEt (3.4 mL, 19.5 mmol, 2.5 equiv.) in CH3CN was added 2-chloroethanol (995 mg, 11.7 mmol, 1.5 equiv.). The resulting mixture was refluxed 7 h (oil temp. 91° C.), then O/N (15 h, oil temp. 83° C.) and 6 h (oil temp. 90° C.) before cooling to rt. After diluting with H2O (30 mL) and sat. NaHCO3 (30 mL), it was extracted with EtOAc (60 mL×2) and washed with H2O and brine. Removal of solvents followed by trituration with MeOH (15 mL) afforded the title compound as a beige solid (1.340 g, 81%). A second trituration of the concentrated mother liquor gave additional 602 mg of crude product as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.43 (t, J=5.0 Hz, 1H), 3.51 (q, J=5.6 Hz, 2H), 3.12-3.07 (m, 4H), 2.55-2.49 (m, 4H, partially overlapping with DMSO signal), 2.41 (t, J=6.0 Hz, 2H); MS ESI 332.9[M+H]+, calcd. for [C12H17IN2O+H]+ 333.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7](C(O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CN([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:11][CH:12]=1)[C:25]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:29])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NCCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCN1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.9 %

Procedure:
500 mg of 4-nitrobenzoic acid is dissolved in 20 ml of dimethylformamide, mixed with 370 μl of triethylamine, 342 mg of N-(3-aminopropyl)-pyrrolidine and 866 mg TBTU, and stirred for 20 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with dichloromethane. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 502 mg of the title compound is obtained.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42](C2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:41][CH:40]1[CH2:76][OH:77])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41][CH:40]1[CH2:76][OH:77])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1CO

Procedure:
(2R) 2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:22]([CH:23]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]3=[O:30])[C:15]([CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2cc(Cl)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a stirred mixture of 2-amino-4-chlorobenzoic acid (5.0 g, 29 mmol) and imidazole (2.4 g, 35 mmol) in acetonitrile (50 mL), was added acetyl chloride (2.5 mL, 35 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (4.8 g, 29 mmol), imidazole (4.4 g, 64 mmol) and triphenyl phosphite (8.4 mL, 32 mmol) and heated to reflux for 22 hours. The suspension was filtered and washed with acetonitrile (50 mL) and water (2×50 mL) to give 3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (6.5 g, 73% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.36 min (99.9%); mp: 291-293° C.; 1H NMR (DMSO-d6) δ 2.16-2.23 (m, 1H, CHH), 2.59-2.72 (m, 5H, CH3, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.29 (dd, J=5, 11 Hz, 1H, NCH), 7.53 (dd, J=2.9 Hz, 1H, Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.03 (d, J=8 Hz, 1H. Ar), 11.07 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.84, 23.53, 30.58, 56.65, 19.06, 125.70, 126.91, 128.07, 139.30, 147.89, 156.74, 159.89, 169.35, 172.58; LCMS: MH=306, 308; Anal Calcd for C14H12N3O3Cl: C, 55.00; H, 3.96; N, 13.74; Cl, 11.60. Found: C, 55.24; H, 3.78; N, 13.74; Cl, 12.01.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:34]=[O:35])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a 3 ml tetrahydrofuran solution of 150 mg (0.36 mmol) of the compound obtained in Example 15, 0.45 ml of n-butyl lithium (1.59M hexane solution 0.72 mmol) was added dropwise at −78° C. After the mixture was stirred at the same temperature for 30 minutes, 33.4 μl (0.43 mmol) of N,N-dimethylformamide was added dropwise to the reaction mixture, followed by stirring the mixture at −78° C. for 2 hours. Then, an aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 73 mg (55%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([NH2:13])=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]2[CH2:20][CH2:21][CH:22]=[CH:23][CH:15]12>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH2:6][CH3:7])=[CH:8][C:9]([N:13]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:10]([F:12])[CH:11]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CCOCc1cc(N)c(F)cc1Br
Solvent: CC(=O)O
Product: CCOCc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Yield: 40.7 %

Procedure:
By the method of Example 2, Step H, 1.61 g (0.00649 mole) of ethyl 2-bromo-4-fluoro-5-aminobenzyl ether and 1.08 g (0.0071 mole) of tetrahydrophthalic anhydride were reacted in 30 ml of glacial acetic acid, yielding 1.01 g of N-(4-bromo-2-fluoro-5-ethoxymethylphenyl)-3,4,5,6-tetrahydrophthalimide as a yellow solid, m.p. 104°-106° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].Cl.N[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.O.[N:28]1C=CC=CC=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:28][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=[CH:17][N:18]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(N)nc1
Agent: Cl
Solvent: O
Product: COC(=O)c1cccnc1NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
5.9 g (26 mmol) of naphthalene-2-sulfonyl chloride were added in portions at room temperature to 4.7 g (25 mmol) of methyl 6-aminonicotinate hydrochloride in 100 ml of dry pyridine. The entire mixture was then stirred at room temperature for 16 h. The reaction solution was then poured onto 500 ml of water and the precipitate obtained was filtered off with suction. 6.4 g (75%) of the product were obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:32]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCOc1cccnc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3cccnc3)cc12

Procedure:
6-[2-(Pyridin-3-yloxy)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 16% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-(2-Chloro-ethoxy)-pyridine.