Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([OH:38])[CH2:40]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCCNC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(O)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxy-piperidine (TCI America) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C33H40N5O3Cl2 [(M+H)+] 624.2503, observed 624.2502.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]1([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]1)[C:8](=[O:15])[N:9]2[CH3:14])=O.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[C:7]2([C:27]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][CH2:23][O:22][C:21]=5[CH:26]=4)[O:17][CH2:16]2)[C:8](=[O:15])[N:9]3[CH3:14])[N:28]=1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)CBr)cccc21
Reactant: NC(N)=S
Solvent: CCO
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3csc(N)n3)cccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.20 g, 0.47 mmol) in anhydrous ethanol (10 mL) was added thiourea (0.039 g, 0.51 mmol) and the reaction mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 10% gradient of methanol in dichloromethane to afford 4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.159 g, 84%) as a pale yellow solid: mp 233-234° C. (dec.) (dichloromethane/methanol); 1H NMR (300 MHz, CDCl3) δ7.44-7.37 (m, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.57-6.42 (br m, 2H), 6.37 (s, 1H), 6.22 (s, 1H), 5.80 (s, 1H), 4.80-4.73 (m, 2H), 4.22-4.07 (m, 4H), 3.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 168.2, 155.7, 144.8, 144.4, 138.1, 129.7, 129.4, 124.3, 121.9, 111.4, 109.4, 105.9, 99.2, 78.4, 77.4, 64.7, 64.0, 58.6, 27.1; MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:17][C:16]=2[CH2:35][N:36]2[CH2:40][CH2:39][O:38][C:37]2=[O:41])[CH:7]=1)[CH3:2].Cl.NO.C([O-])(=O)C.[K+]>CO>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:35][N:36]2[CH2:40][CH2:39][O:38][C:37]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N=C(c3ccccc3)c3ccccc3)cc2CN2CCOC2=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reaction time: 8 h

Procedure:
To {3-[4-(benzhydrylidene-amino)-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (2.2 mmol) in MeOH was added hydroxylamine hydrochloride (4.4 mmol) and potassium acetate (4.4 mmol), and the reaction was stirred overnight. The mixture was worked-up, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:63]/[O:64]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:61](=[O:62])[N:32]3[C:33]([C:45]([O:47]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:46])=[C:34](/[CH:37]=[CH:38]\[C:39]4[S:43][N:42]=[N:41][C:40]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O.Cl.C(=O)(O)[O-].[Na+:92]>>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:63]/[OH:64])/[C:27]([NH:29][CH:30]2[C:61](=[O:62])[N:32]3[C:33]([C:45]([O-:47])=[O:46])=[C:34](/[CH:37]=[CH:38]\[C:39]4[S:43][N:42]=[N:41][C:40]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1.[Na+:92]
Reactant: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cc1nnsc1/C=C\C1=C(C(=O)[O-])N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (1.38 g, 1.2 mmol) was stirred at room temperature for 1 hour by addition of formic acid (14 ml). Concentrated hydrochloric acid (0.11 ml) was added to the reaction solution and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was cleansed with ether thereby a yellow powder product was obtained. This one was dissolved in aqueous sodium bicarbonate solution and purified by HP-20 column chromatography thereby sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (79 mg) was obtained.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][CH2:10][C:11](=[O:24])[C:12]#[C:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+].C(O)CC>[C:3]1([CH2:9][CH2:10][C@H:11]([OH:24])[C:12]#[C:13][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:21]([CH3:22])[CH3:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[Si](C#CC(=O)CCc1ccccc1)(C(C)C)C(C)C
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCCO
Product: CC(C)[Si](C#C[C@@H](O)CCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Following a modified procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)); Potassium hydroxide (8.5 mg, 0.15 mmol, 1.2 mol %) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (80.7 mg, 0.127 mmol, 1 mol %) were added to) PrOH (110 ml) and the resultant mixture was stirred for 2 min at r.t. 5-Phenyl-1-(triisopropylsilyl)pent-1-yn-3-one 84 (4.0 g, 12.7 mmol, 1 eq.) was added via syringe and the mixture was stirred at r.t. for 45 min. The mixture was concentrated in vacuo to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et2O (20:1 to 10:1), giving the title product 85 as a clear, colourless oil (4.0 g, 99%). The enantiomeric excess was determined to be 99% via HPLC analysis of its derivative 87. Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)).
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[OH:2][CH2:1][C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CC[C@H](O)C=C12

Procedure:
A solution of 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (2.30 g, 5.33 mmol), Example 3, part E, in methylene chloride (70 mL) at -78° C. is treated with diisobutylaluminum hydride (1.5M in toluene, 15 mL, 22.5 mmol). After 20 minutes the reaction is quenched with methanol (4 mL), methylene chloride added (150 mL), washed with 2N NaOH and water, dried over MgSO4 and concentrated to give crude 17β-hydroxymethyl-3β-hydroxy-6-t-butylcarboxy-6-azaandrost-4-ene of sufficient purity to carry on to the following steps; yield: 2.16 g (99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[C:11]1[C:12]2[N:13]([CH:18]=[CH:19][N:20]=2)[N:14]=[C:15]([Cl:17])[CH:16]=1>CN(C=O)C>[Cl:17][C:15]1[CH:16]=[C:11]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2([CH3:7])[CH3:1])[C:12]2[N:13]([CH:18]=[CH:19][N:20]=2)[N:14]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CC1(C)CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCCN1c1cc(Cl)nn2ccnc12
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 2,2-dimethylpyrrolidine (0.248 g, 2.5 mmol) in DMF (8 mL) was added NaH (0.060 g, 60% dispersion in mineral oil, 2.5 mmol) and stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.233 g, 1 mmol) under N2. The mixture was stirred at room temperature for 16 h. Then it was partitioned between 15 mL of saturated NH4Cl solution and 15 mL of ether. The organic layer was washed with water (10 mL×3) and saturated NaCl solution (10 mL×3), dried over NaSO4, concentrated in vacuo, and purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-8-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine (0.140 g, 22%) as a light brown solid. LC-MS: [M+H]+, 251.1, tR=1.698 min.
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:17])[CH2:7][CH2:8][CH2:9][CH:10]1[O:15][CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)=[CH2:19].[Mg].C(Cl)=C>O1CCCC1>[OH:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH2:9][CH2:8][CH2:7][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17])[CH:18]=[CH2:19]
Reactant: CC(CCCC1CCCC(O)O1)OC(C)(C)C
Reactant: C=C[Mg]Cl
Agent: C=CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-[4-(t-butoxy)pentyl]-tetrahydropyran-2-ol (5 g.) in tetrahydrofuran (50 ml.) was added within 30 minutes at 5° to a solution of vinyl magnesium chloride in tetrahydrofuran, prepared from magnesium (2.0 g.) and 4 g. of vinyl chloride, dissolved in tetrahydrofuran (50 ml.). After stirring overnight at room temperature, the reaction solution was treated with ammonium chloride-ice and then extracted with chloroform (3 times, each time 100 ml.). The organic phase was washed with water, dried and evaporated in vacuo giving crude 3,7-dihydroxy-11-(t-butoxy)-dodec-1-ene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(O)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)cccc1C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 90.1 %

Procedure:
To a solution of (3-Benzyloxy-2-methyl-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (624, 0.12 g, 0.35 mmol) in tetrahydrofuran (15 mL) was added Dess-Martin periodinane (0.37 g, 0.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes, then quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1848, 108 mg, 90%). MS (ESI) [M+H+]+=343.22.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:18])OCC[O:14]2)=[CH:9][CH:8]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>C1COCC1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([B:23]([OH:24])[OH:22])=[CH:8][CH:9]=1)(=[O:14])[CH3:18]
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (81.6 ml) was added dropwise to a stirred solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (30.0 g) in dry THF (400 ml), under nitrogen, at -75° C. After a period of 1.5 h, triisopropylborate (31.2 ml) was added dropwise at -75° C. The reaction was allowed to warm to room temperature over a 3 h period. Hydrochloric acid (2N; 200 ml) was added and the reaction was allowed to stand at room temperature overnight. The solvent was evaporated and the residue was purified by FCC eluting with ether to give a white solid which was purified by crystallisation from water (200 ml) to give the title compound (14.52 g) as a white crystalline solid m.p. 268°-270° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].C[N+](C)(C)C.[OH-].C(Br)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[C:2]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: BrCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Approximately 10 gs (6.17×10-2 moles) of 4-acetoxystyrene was added to a 25 wt % solution of TMAH (51 mL). After 15 minutes of stirring a clear yellowish solution was obtained. About 10.6 gs (6.17×10-2 moles) of benzyl bromide was added to this solution with stirring. Slow formation of product crystals was observed. Reaction was complete as seen by thin layer chromatography after about 5 hours. The crystals were filtered-off, washed with distilled water, and sucked dry. In this way, 10.5 gs (81% yield) of pure desired product was obtained. Analysis of the product indicated:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1)[CH3:21]
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Reactant: CCO
Product: CCOc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H](CC1C=CC=CC=1F)C(O)=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1F)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-fluorophenyl)propionic acid as a dicyclohexylammonium salt (5.57 g; 18.73 mmol) was dissolved in methylene chloride (30 mL) and washed with an aqueous solution of sodium hydrogen sulfate (10%; 30 mL). The organic phase was dried (magnesium sulfate) and filtered. 1-Hydroxybenzotriazole hydrate (2.53 g; 18.73 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.75 g; 19.6 mmol) were added to the filtrate and the mixture was stirred for 15 min at room temperature. Methylamine (40% in methanol; 0.53 g; 17.0 mmol) and diisopropylethylamine (3.2 mL; 18.7 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3.5×40 cm) using ethyl acetate/heptane (2:1) as eluent to afford 2.4 g of N-((1R)-2-(2-Fluorophenyl)-1-methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=NO)[C:6](=[O:13])[NH:7]2.CN(C=[O:21])C>Cl.[Pd]>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([OH:21])[C:6]([OH:13])=[N:7]2
Reactant: Cc1cc(C)c2c(c1)NC(=O)C(=NO)C2=O
Reactant: CN(C)C=O
Agent: [Pd]
Agent: Cl
Product: Cc1cc(C)c2c(O)c(O)c(O)nc2c1
Reaction time: 12 h
Yield: 50 %

Procedure:
The procedure of Baker and Almaula, J. Org. Chem. 27:4672-74 (1962), was adapted. A mixture of 5,7-dimethylquinoline-2,3,4-trione-3-oxime (45 mg, 0.21 mmol) and 30% Pd/C (10 mg) in DMF (2 mL) and 4N HCl (2 mL) was hydrogenated at 50 psi for 12 h. A crystalline colorless solid was observed in the reaction mixture. The mixture was filtered and the solid was stirred with acetone/methanol (1:1) and filtered to remove the black catalyst. The acetone/methanol solution was added into the 1N HCl solution (10 mL) to give white crystals. It was filtered and washed with water (1×1 mL), and dried to leave 21 mg of the title compound (50%), which is pure by NMR. mp 280°-2° C. IR (KBr, cm-1): 3452, 3178, 3108, 1663, 1621, 1585. 1H NMR (DMSO-d6): δ 2.248 (s, 3H); 2.638 (s, 3H); 6.704 (s, 1H); 6.876 (s, 1H); 8.595 (s, 1H); 9.542 (s, 1H); 11.424 (s, 1H). HRMS: calcd for C11H11NO3 m/z: 205.0738; found: 205.0729. Purity:>99% by HPLC (tautomers 71.5% and 28.4%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][CH2:26][CH2:27]I>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:27][CH2:26][F:25])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FCCI
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.0 g, 3.2 mmol) in 20 mL of DMF was added to a suspension of sodium hydride (0.16 g, 3.9 mmol) in 20 mL of DMF and stirred for 30 minutes. 2-Fluoroethyl iodide (1.1 g, 6.4 mmol) was added, and the mixture was warmed to 50° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine and dried over magnesium sulfate. The solution was concentrated to give 0.73 g of the title compound as a solid, mp 145-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH2:26])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH:26][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ncc(N)cc1CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(NS(=O)(=O)c2cccnc2Cl)cc1CNC(=O)OC(C)(C)C
Yield: 95 %

Procedure:
The title compound (2.12 g, 4.94 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [OH:1][CH:2](C)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:27]I>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:27])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: CC(O)CCCNS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CI
Product: CN(CCCCO)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Using a method analogous to that described in Example 4, 4′-trifluoromethylbiphenyl-4-sulfonic acid-(4-hydroxypentyl)-amide and methyl iodide were reacted to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:28]([Zn+])[CH:29]([CH3:31])[CH3:30]>>[CH2:28]([C:16]1[CH:15]=[C:14]([C:20]([F:22])([F:21])[F:23])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Product: CC(C)Cc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a colorless oil from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45) and iso-butyl zinc bromide. MS (ES+): 313 (base, M+H).
Reaction SMILES: CO.C([NH2:7])CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:7])=[O:28])[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Reactant: CCCCN
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)NCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1:6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction mixture was then allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 5 ml of tetrahydrofuran were added to the residue. 0.32 ml of trimethylsilyl isocyanate was then added dropwise to the resulting mixture, whilst ice-cooling, and then the mixture was stirred at room temperature for 3 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 1:0 and 5:1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 80 mg of the title compound as yellow crystals, melting at 74 to 78° C.