Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl:29][CH2:30]Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([O:22][CH2:30][Cl:29])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)O)C(C)C
Reactant: ClCCl
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C

Procedure:
2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid was esterified by the method described in Example A-I-1, step d. The title compound (2.96 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.85.
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.[S: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>[S: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: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cc2ccccc2s1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

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-Benzothiophene-2-sulfonyl chloride (23 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 (1.9 mg). MS m/z 385 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:10][CH2:9]1.O.C([O-])([O-])=O.[K+].[K+]>CO>[OH:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:13][CH2:12]1
Reactant: O=C(O[C@H]1CC[C@@H](N2CCCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1CCCCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve cis-4-nitro-benzoic acid-4-(2-oxo-piperidin-1-yl)-cyclohexyl-ester (5.0 g, 14.4 mmol) in methanol (150 mL), add water (20 mL), K2CO3 (8.7 g, 0.06 mol) and stir the reaction mixture at room temperature for 18 hours. Extract the reaction mixture with DCM (2×100 mL), dry the organic layer over Na2SO4 and remove the solvent to obtain cis-1-(4-hydroxy-cyclohexyl)-piperidin-2-one as clear oil (6.0 g). Combine cis-1-(4-hydroxy-cyclohexyl)-piperidin-2-one (6.0 g, 0.03 mol), imidazole (3.1 g, 0.05 mol), tert-butyl chloro dimethyl silane (6.9 g, 0.05 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (150 mL) and dry the organic layer over Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a clear oil (3.4 g, 76%): MS (ES+) m/z=312 (M+H)+.
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][N:9]([S:12]([CH2:15][CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[CH3:26])(=[O:14])=[O:13])[CH2:8][CH2:7]2)[O:5]CC1>CC(C)=O>[CH3:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[CH2:16][CH2:15][S:12]([N:9]1[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]1)(=[O:14])=[O:13])[C:21]([OH:23])=[O:22]
Reactant: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A 6 M aqueous hydrochloric acid solution (217.9 ml, 1307.4 mmol) was slowly added to a suspension of 4-[2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-ethyl]-3-methyl-benzoic acid (16.1 g, 43.58 mmol) in acetone (485 ml) at 0° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered off, and the filtrate was then concentrated under reduced pressure. The precipitated solid was filtered off again. The solids filtered off were combined and dried to give 3-methyl-4-[2-(4-oxo-piperidine-1-sulfonyl)-ethyl]-benzoicacid as a white solid (13.62 g, 91.8%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([N:1]=[C:15]=[O:16])=[C:3]([F:13])[CH:4]=1
Reactant: Nc1c(F)cc(Cl)c2c1OCCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2c1OCCC2
Yield: 99.8 %

Procedure:
By the method of Example 1, Step F, 2.2 grams (0.011 mole) of 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran and 2.2 grams (0.011 mole) of trichloromethyl chloroformate were reacted in 50 mL of toluene, yielding about 2.5 grams of 5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37](=[CH2:41])[CH2:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH2:38][C:37]([CH3:41])=[CH2:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: C=C(C)CCO
Agent: N
Product: C=C(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-3-butene-1-ol in place of isobutanol (yield: 0.1327 g, 91%). mp 109-111° C. 1H NMR (300 MHz, DMSO d6) δ 1.61 (s, 3H), 2.32 (t, J=7 Hz, 2H), 3.30 (s, 3H), 4.56 (t, J=7 Hz, 2H), 4.63 (bs, 1H), 4.68 (bs, 1H), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.50; H, 5.00; N, 6.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[BH4-].[Na+]>O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C@@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H](O)CCl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-1-(2,5-difluorophenylmethyl)-3-chloro-2-oxopropylcarbamic acid tert-butyl ester (3.56 g, 11 mmol) in a solution of 9:1 THF:water (150 mL) at 0° C. is added NaBH4 (0.49 g, 13 mmol, 1.2 eq) and stirred for 5 min. The reaction mixture is concentrated under reduced pressure to a white solid which is suspended in a mixture of water and ethyl acetate. This biphasic mixture is cooled to 0° C. and quenched slowly with 2M NaHSO4 until pH˜2 and the layers rapidly separated. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford a white solid as a mixture of diastereomers (3.5 g, 13 mmol, ˜5:2 R,R:R,S). The crude material was purified using General Purification Procedure C to afford the title compound as a single diastereomer of a white solid (2.2 g, 6.6 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=2)[NH:26][CH:25]=1.C(Br)(Br)(Br)[Br:37]>C(#N)C>[Br:37][CH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=2)[NH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of triphenylphosphine (6.70 g, 0.025 mol) in 80 mL of acetonitrile was added a solution of 3-[3-hydroxypropyl]-5-nitro-1H-indole (Example 3) (4.30 g, 0.020 mol) in 75 mL of acetonitrile, followed by a solution of CBr4 (9.00 g, 0.027 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 3 h and then it was evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane, 1:9 then 1:4) to give the title compound (4.60 g, 84%) as a solid, mp 92°-95° C.: IR (neat) 3420, 1330 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ8.59 (d, J=2.1 Hz, 1H), 8.40 (br s, 1H), 8.13 (dd, J=9.0, 2.2 Hz, 1H), 7.40 (d, J=9.1 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 3.45 (t, J=6.4 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.26 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:21]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2,2,2-trifluoroethanamine via General Procedure 13. The product was purified via reverse phase HPLC to give 10.4 mg of 254. MS (Q1) 462.7 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (87 mg, 0.19 mmol) is treated with acid chloride 6 (58 mg, 0.23 mmol) using Method D to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:9]5[N:8]6[C:4]([S:5][CH:6]=[CH:7]6)=[N:3][C:2]=5[CH3:1])=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: Cc1nc2sccn2c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc2sccn2c1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 20 h

Procedure:
A mixture of 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61 mg, 0.33 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, (133 mmol), EDC (77 mg 0.39 mmol) and IIOAt (54 mg, 0.39 mmol) was stirred in DMF (3 ml) at 80° C. for 1 h then at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified by preparative LC/MS to give 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (LC/MS Basic: Rt 2.56 [M+H]+ 463).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([NH:11][S:12](Cl)(=[O:14])=[O:13])([CH3:10])[CH3:9].C(N)(C)C.S(Cl)(Cl)(=O)=O.[Sb](Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([O:7][S:12](=[O:14])(=[O:13])[NH:11][CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: Oc1ccccc1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)N
Solvent: Cc1ccccc1
Product: CC(C)NS(=O)(=O)Oc1ccccc1
Yield: 32 %

Procedure:
This compound was prepared according to the procedure of Example 37. Thus a solution of 16.2 g (0.17 mole) of phenol and 33.0 g (0.21 mole) of N-isopropylsulfamoyl chloride (prepared from isopropylamine, sulfuryl chloride and antimony pentachloride by the procedure of Example 2, part a) in 150 ml of toluene gave a dark oil which was purified by column chromatography on silica gel using ethyl acetate-hexanes (1:16) to elute the product. Desired fractions were combined and concentrated to yield 11.7 g (32%) of the title compound as a light-yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[C:40]([O:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45](=[O:49])[CH2:46][N:47]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CC(=O)OC(C)(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added sarcosine tert butyl ester hydrochloride (84 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 577 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[NH:12]C(NCCN)=S.Cl>CO>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[NH:12][N:9]1[CH2:10][CH2:6][N:7]=[CH:8]1
Reactant: Cc1cc(NC(=S)NCCN)c(C)c2[nH]cnc12
Agent: Cl
Solvent: CO
Product: Cc1cc(NN2C=NCC2)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of N-(4,7-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea (0.77 g) and cupric acetate (0.81 g) in methanol (100 mL) is stirred at 65°-70° C. for 40 minutes. The mixture is cooled to room temperature, NaHS.xH2O is added and the resulting mixture is stirred for 10 minutes at room temperature. The mixture is acidified to pH=3 with 1N HCl and filtered on Celite. The filtrate is basified to pH=9 with 50% sodium hydroxide and rotary evaporated. The syrupy residue is diluted with water (20 mL) and lyophilized. The solid residue is purified by flash chromatography on a short pad of silica gel, eluting first with 10% methanol/chloroform containing 0.1% ammonium hydroxide, then 30% methanol/chloroform containing 1% ammonium hydroxide. The product-containing fractions are collected and rotary evaporated. The residue is diluted with water (5 mL) and lyophilized to afford 4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole as a yellow glassy solid. A fumarate salt is obtained by treating a solution of 4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole in methanol (20 mL) with fumaric acid (0.278 g). The mixture is heated to achieve solubilization, then cooled to room temperature. The precipitate is filtered and recrystallized twice from methanol/water to afford 4,7-dimethyl-5-(2-imidazolinylamino)benzimidazole sesquifumarate.
Reaction SMILES: [Cl:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11]>C(O)C.Cl>[ClH:1].[OH:11][C:10]1[N:12]=[C:6]([CH3:7])[C:2]([Cl:1])=[C:3]([CH3:4])[N:9]=1
Reactant: NC(N)=O
Reactant: CC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc(O)nc(C)c1Cl
Temperature: -10 °C

Procedure:
A solution of 134.5 g (1 mole) of the 3-chloropentane-2,4-dione prepared as in (i) and 75 g (1.25 moles) of urea in 800 ml of ethanol and 100 ml of concentrated hydrochloric acid was heated for 10 hours under reflux. It was then cooled to -10° C., whereupon a precipitate formed, which was filtered off and dried. 114 g (58% of theory of 2-hydroxy-5-chloro-4,6-dimethylpyrimidine hydrochloride were obtained in the form of colorless crystals of melting point >210° C. ##STR57##
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:21]=[CH:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:24]1[N:18]2[C:17](=[O:33])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH:21]=[CH:20][C:19]2=[N:22][C:23]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)c(Cl)n12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
N-chlorosuccinimide (32.9 mg, 0.25 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (75 mg, 0.22 mmol) in DMF (3.5 mL). The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield 3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (46 mg, 56% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm 5.12 (s, 2H), 6.62 (d, J=7.9 Hz, 1H), 6.98 (tt, J=7.4, 0.9 Hz, 1H), 7.03-7.07 (m, 2H), 7.06 (d, J=7.6 Hz, 1H), 7.17-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.35-7.43 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:14][C:11]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(NC(=O)OC(C)(C)C)CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
tert-Butyl (1-benzyl-4-methyl-4-piperidinyl)-carbamate obtained in Example 10-4 (1.01 g) was dissolved in methanol (20 mL), and 20% Pd(OH)2 on carbon (300 mg) was added. The mixture was stirred under hydrogen atmosphere (4 atm) at 20° C. for 2 hrs. The reaction mixture was diluted with ethyl acetate, filtered through a pad of Celite, and concentrated. The residual solid was triturated with hexane to give the title compound as white crystals (425 mg)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2ccccc2[nH]1
Product: COCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 86.8 %

Procedure:
Using 2-methoxymethyl-1H-benzo[d]imidazole (Journal of Organometallic Chemistry, 2008, vol. 26, p 3889; 244 mg, 1.51 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (550 mg, 1.54 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (576 mg, 87%) was obtained.
Reaction SMILES: [CH2:1]1[CH:8]2[CH:2]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](=O)[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]1[CH:8]2[CH:2]1[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](=[N:19][OH:20])[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12
Reactant: O=C1c2ccccc2C2CC2c2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2C2CC2c2ccccc21

Procedure:
A solution of 6.6 g (0.03 mole) of 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one, 8.4 g (0.12 mole) of hydroxylamine hydrochloride in 120 ml of pyridine was held at reflux for 18.5 hrs. The solvent was evaporated under reduced pressure and the residue was dissolved with a mixture of water and methylene chloride. The layers were separated and the organic layer was in turn washed with 10% hydrochloric acid, and saturated brine, dried and solvent evaporated to give 7.4 g of crude 1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime, mp 201° (ex. MeOH, dried at 110°/0.1 mm). The NMR spectrum in CDCl3 -DMSO-d6 : a singlet at δ10.9 (1H), multiplet at 6.9-7.6 (8H), multiplet at 2.1-2.6 (2H) and multiplet at 1.3-1.8 (2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[C:5]([NH2:18])=[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: Nc1nc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c(-c2ccco2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(NC(=O)c2ccc(Cl)nc2)c(N)c(-c2ccco2)n1

Procedure:
A solution of N-(2-amino-6-(2-furyl)-5-nitropyrimidine-4-yl)-6-chloropyridine-3-carboxamide (153 mg, 0.423 mmol) and 10% Pd/C (82 mg, 42.3 μmol) in EtOH (20 mL) and EtOAc (5 mL) was stirred under an hydrogen atmosphere for 3 h, filtered through Celite and concentrated in vacuo to give N-(2,5-diamino-6-(2-furyl)pyrimidin-4-yl)-6-chloropyridine-3-carboxamide as a yellow oil. A solution of this product in EtOH (5 mL) and 2-M HCl (5 mL) at 0° C. was treated dropwise with an ice-cold solution of sodium nitrite (87 mg, 1.27 mmol) in water (2 mL). The mixture was stirred at 0° C. for 1 h, stirred at room temperature for 1 h, neutralised with 5-M NaOH, stirred for 16 h and the resulting solid was filtered to give title compound (40 mg, 28%) as a brown solid.