Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6]([O:9]C)=[N:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)cn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c[nH]c(=O)c2c(-c3csc(C(N)=O)c3)cn(C3CCCC3)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 4-(7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (310 mg) in acetonitrile (40 mL) were added sodium iodide (254 mg) and chloro(trimethyl)silane (536 mL), and the mixture was stirred at 80° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (143 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[NH:29][C@@H:26]([CH2:27][CH2:28]1)[CH2:25][O:24][CH2:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:29]3[C@H:22]4[CH2:28][CH2:27][C@@H:26]3[CH2:25][O:24][CH2:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1C[C@H]2COC[C@@H]1N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1[C@@H]2CC[C@H]1COC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (904316-92-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.6 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of tert-butyl 4-(4-chlorophenyl)cyclohexylcarbamate (0.760 g, 2.45 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml), and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated, taken up in water, and 1M NaOH was added until the pH was >13. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 371 mg of the title compound (72.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)[C:23]=3[CH2:22][C:9]2=1
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Reactant: CO/N=C/c1ccc2c(c1Cn1ccnc1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1Cn1ccnc1)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 6.5 %

Procedure:
The amine 8 (0.905 g, 3.55 mmol) and oxime ether 13c (0.41 g, 1.6 mmol) were mixed with concentrated hydrochloric acid (8 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3), and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was diluted in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=10:90:2) to afford the final pure product 14c as a light brown solid (0.0419 g, 6.6%): mp 250° C. (dec). IR (KBr) 2961, 1496, 1413, 1207, 1020 cm−1; 1H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 7.84 (s, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.90 (s, 1H), 6.15 (s, 2H), 5.33 (s, 2H), 4.08 (s, 2H), 3.99 (s, 3H), 3.92 (s, 3H); low resolution ESIMS m/z (rel intensity) 402 (MH+, 100), 334 (15). Anal. (C23H19N3O4.1.5H2O) C, H, N.
Reaction SMILES: Cl.[I:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br>>[CH3:22][O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][N:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:3]([I:2])=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: Ic1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: Cl
Product: COC(=O)CCCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Yield: 94.6 %

Procedure:
The title compound (300 mg, 85%) was prepared from the compound from step 2 of Example 14 (300 mg, 0.66 mmol) and 4-bromo-butyric acid methyl ester (153 mg, 0.85 mmol) by the procedure described in step 3 of Example 4: MS (ESI) m/z 481 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.86 (m, 2H), 2.36-2.44 (m, 4H), 2.60 (t, J=4.8 Hz, 4H), 3.15 (t, J=4.8 Hz, 4H), 3.68 (s, 3H), 6.70 (s, J=8.8 Hz, 2H), 6.92 (m, 4H), 7.55 (d, J=8.8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: ClCCl
Solvent: O
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Yield: 67.3 %

Procedure:
A solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (5.18 g, 19.5 mmol) and TEA (10.9 mL, 78.0 mmol) in dichloromethane (100 mL) was treated with Tf2O (7.20 mL, 42.8 mmol) at −78° C. for 1 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane. The organic phases were separated, dried (Na2SO4), and concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=4:1), affording the title compound (5.23 g, 67%). 1H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 5.60-5.58 (m, 1H), 4.84 (s, 2H), 3.78-3.74 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (s, 3H), 1.91-1.88 (m, 2H), 1.74-1.68 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])[CH3:43].C(N(CC)CC)C>ClCCl>[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1)[CH3:43]
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26) (37 mg, 0.099 mmol) was combined with 1-hydrobenzotriazole hydrate (23.0 mg, 0.149 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29.0 mg, 0.149 mmol), and beta-alanine ethyl ester hydrochloride (18.0 mg, 0.119 mmol). Anhydrous dichloromethane (5 mL) was added followed by triethylamine (0.027 mL, 0.198 mmol). The solution was stirred at room temperature for 3 d before partitioning between ethyl acetate and aq. sat. ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (37.9 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.2 Hz, 2 H) 7.59 (t, J=3.9 Hz, 2 H) 7.46-7.52 (m, 3 H) 7.37-7.45 (m, 1 H) 7.11-7.19 (m, 1 H) 6.75 (t, J=5.8 Hz, 1 H) 5.32 (dd, J=9.7, 6.7 Hz, 1 H) 4.75 (d, J=6.6 Hz, 1 H) 4.10-4.21 (m, 2 H) 3.70 (q, J=6.0 Hz, 2 H) 2.55-2.74 (m, 3 H) 2.29 (s, 3 H) 1.96 (ddd, J=11.1, 8.2, 2.9 Hz, 1 H) 1.75-1.84 (m, 1 H) 1.64-1.73 (m, 2 H) 1.26 (m, 3 H) 1.16 (s, 3 H) 1.09 (s, 3 H); MS (M+1): 474.7.
Reaction SMILES: [CH:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:10][S:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The general method of procedure A was followed with cyclohexanesulfonamide (1.89 g), acetone (5 ml), 1N sodium hydroxide (11.6 ml). After stirring overnight at room temperature, the mixture was cooled in an ice bath and 4-chlorophenyl isocyanate (1.89 g) dissolved in acetone (5 ml) was added. The mixture was warmed to room temperature and stirred two days, filtered, and the separated white solid washed with water. The filtrates were combined and treated with glacial acetic acid (1 ml) followed by addition of water. The resulting solid was collected by filtration, washed with water and air dried to provide 2.57 g of a tan powder.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(F)cc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1Cl
Yield: 8.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chloro-4-fluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-biphenyl-2-carboxylic acid (8 mg, 8%). LCMS analysis indicated that the material was 93% pure, as measured by UV at 214 nm. LRMS m/z 479.7 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[F:23][CH:24]([F:31])[N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH:24]([F:31])[F:23])[CH:29]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(C(F)F)c1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C(F)F)c3)ncc2Cl)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.076 g, 0.225 mmol), 1-(difluoromethyl)-1H-pyrazol-4-amine A28 (0.030 g, 0.23 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.023 mmol) in 1,4-dioxane (4.0 mL) was stirred in a microwave reactor at 120° C. for 2 hours. The volatiles were evaporated in vacuo and the residue was purified by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-5% MeOH in DCM). Fractions containing suspected product were combined and the solvent removed in vacuo to give a residue that was purified further by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.). Fractions containing suspected product were combined, the solvent was removed in vacuo and the resulting solid purified by prep-LCMS to give the title compound 34 as a white solid (0.005 g, 5%). LCMS-B: rt 3.41 min; m/z 433 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:29](=[O:30])[C:28](Cl)=[C:27]([Cl:32])[CH:26]=[N:25]2)[CH:20]=[CH:21][C:22]=1[F:23]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:29](=[O:30])[C:28]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:27]([Cl:32])[CH:26]=[N:25]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CCCCO
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c(Cl)cnn(-c2ccc(F)c(F)c2)c1=O
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a stirred, room temperature solution of n-butanol (0.81 g, 10.93 mmol, 1.1 equiv.) in THF (20 mL) was slowly added 1.0 M sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol, 1.2 equiv.). The reaction mixture was stirred for 0.5 hours, then it was transferred to a solution of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone (2.88 g, 10.4 mmol, 1.0 equiv.) in THF (80 mL). The resulting reaction mixture was stirred for 0.5 hours at room temperature to provide the title compound (2.5 g, 79.4%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Cc2c(I)cccc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Product: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Temperature: 23 °C
Yield: 65.2 %

Procedure:
A mixture of 4-iodooxindole (404.1 mg, 1.56 mmol) (see Fukuyama, supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) was treated with 2 drops of piperidne. The reaction mixture was heated at reflux for 24 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide pure (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (341.8 mg, 65%) as a yellow solid which was used without further purification:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N#N.[Li]CCCC.[CH2:39]=[O:40]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH2:39][OH:40])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COC(=O)C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CO)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A solution of tert-butyl 4-(5-(1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)pyrimidin-2-yl)piperazine-1-carboxylate (650 mg, 1.5 mmol) in THF (20 mL, dry) was cooled to −78° C. and protected with N2. Another solution of n-BuLi (1.5 M, 3 mL, ˜4.5 mmol) in THF was added to the above cooled solution during 5 min. The reaction mixture was stirred at −78° C. for 1 h, followed by the addition of paraformaldehyde (405 mg, 15.0 mmol) in one portion under −78° C. This solution was stirred at RT overnight. The reaction was quenched by saturated aqueous NH4Cl (50 mL) and water (50 mL), and extracted with EtOAc (50 mL*4). The combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE:EA (4:1) to obtain the title compound as a yellow thicky oil (300 mg, 44% yield). MS (ES+) C23H29FN4O5 requires: 460. found 461 [M+H]+; purity: 93% (UV214).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.O>[C:14]([C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:16])=[O:3])([CH3:13])[CH3:12])#[N:15]
Reactant: CCOC(=O)c1cccc(C(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg 3-(1-Cyano-1-methyl-ethyl)-benzoic acid ethyl ester and 165 mg sodium hydroxide in 1 ml ethanol and 0.5 ml water were stirred 2 hrs at RT. 20 ml water were added and the pH was adjusted to 1-2 by addition of conc. hydrochloric acid. The title product precipitated and was isolated by filtration, washed with water and dried, yielding 184 mg.
Reaction SMILES: O.[N:2]1[C:15]2[C:6](=C[CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[O-:18][Mn](=O)(=O)=O.[K+]>O>[CH:10]1[C:9]2[C:8](=[O:18])[C:6]3[C:15](=[N:2][CH:3]=[CH:4][CH:5]=3)[C:14]=2[N:13]=[CH:12][CH:11]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1c2cccnc2-c2ncccc21
Yield: 0 %

Procedure:
To a boiling solution of phenanthroline monohydrate (2.2 g, 11.1 mol) and KOH (2 g, 35.5 mol) in water (130 ml), a hot solution of KMnO4 (5 g, 31.5 mol) in water (80 ml) was added dropwise over ca. 1 h. The mixture was refluxed for another 2 h, and then filtered hot. The orange filtrate was cooled and extracted with chloroform, the combined organic extracts were dried over anhydrous Na2SO4. After solvent removal, the crude product was further purified by column chromatography on silica gel using acetone/petroleum ether (2:1) as the eluent, the product was isolated as a yellow solid (980 mg, 48%). 1HNMR (ACETONE-D6,400 MHz): δ=8.80(d, J=5.0 Hz, 2H), 8.06 (d, J=7.5 Hz, 2H), 7.50 (dd, J1=7.5 Hz, J2=5.0 Hz, 2H). HRMS calcd for 182.1782, found 182.0369.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:13][C:12]([CH3:14])=[C:11]2[C:7]=1[CH2:8][C@H:9]1[C:15]([CH3:17])([CH3:16])[C@H:10]12)=[O:5].[CH2:19]([Mg]Cl)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:20][CH2:19][C:4]([C:6]2[S:13][C:12]([CH3:14])=[C:11]3[C:7]=2[CH2:8][C@H:9]2[C:15]([CH3:17])([CH3:16])[C@H:10]23)=[O:5])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Product: Cc1sc(C(=O)CCc2ccccc2)c2c1[C@H]1[C@@H](C2)C1(C)C

Procedure:
3-Phenyl-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]-pentalen-4-yl)-propan-1-one is prepared by reacting (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-lene-4-carboxylic acid methoxy-methyl-amide with phenethyl magnesium chloride in analogy to Example 48; LC-MS: tR=1.15, [m+1]+=311.00.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:20])(=[O:19])[OH:18])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[OH-].[Na+].N(C)(C)C.COS(O[Na:49])(=O)=O>CO.O>[CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:18])(=[O:19])[O-:20])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[Na+:49]
Reactant: COS(=O)(=O)O[Na]
Reactant: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Agent: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)ethyl)-phenylsulfamic acid (75) (150 g, 0.272 mmol) in methanol (1.2 L) was added 50% NaOH (11.3 g, 0.272 mol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at rt for 30 min and then concentrated under reduced pressure to give the crude product, which contained a small amount of Me3N and MeOSO3Na. To a stirred slurry of the crude product (75 g) in H2O (150 mL) was added aq. NaOH (2 g, 0.05 mol; in 50 mL H2O) in dropwise at room temperature. The slurry was continued to stir for 20 min, filtered and washed with water (10 mL) and ethyl ether (50 mL). Then the filter cake was dried under reduced pressure at 50° C. to give 62 g (83%) of the desired compound. LC/MS (M−1): 531; H-NMR (300 MHz, CD3OD) δ: 7.21-6.98 (m, 10H), 5.40-5.36 (t, 1H, J=6.9 Hz), 4.38-4.34 (t, 1H, J=7.5 Hz), 3.61 (s, 3H), 3.24-3.23 (m, 1H), 3.11-3.01 (m, 2H), 2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5 Hz); HPLC: 98.5%.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10]([OH:16])(O)[C:11]([F:14])([F:13])[F:12])[O:3]1>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[O:16][C:6](=[O:8])[CH:5]=1
Reactant: CC1(C)OC(=O)C=C(CC(O)(O)C(F)(F)F)O1
Solvent: Cc1ccccc1
Product: O=c1cc(O)cc(C(F)(F)F)o1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2,2-dimethyl-6-(3,3,3-trifluoro-2,2-dihydroxy-propyl)-[1,3]dioxin-4-one (example C.22 step 1) (70 g, 273 mmol) in toluene (500 mL) was placed in a preheated (135° C.) oil bath, needed 10 min to reflux, then was refluxed for 25 min while distilling off about 150 mL of solvent. The hot solution was concentrated in vacuum to about 300 mL, some heptane was added, cooled to 23° C., filtered the precipitate off, washed with little cold toluene and dried in HV to give the title compound a light yellow solid (17.93 g, 36%). MS (ISN) 179.1 [(M−H)−].