Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2=[CH:6][CH2:7][CH2:8][C:9](=[O:11])[N:10]=[C:4]2[CH:3]=1.Cl.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17].[OH-].[Na+]>CO.O.C(N(CC)CC)C.C(Cl)Cl>[C:9]([NH:10][C:4]1[CH:3]=[C:2]([F:1])[C:13]([CH3:14])=[CH:12][C:5]=1[CH2:6][CH2:7][CH2:17][C:16]([OH:19])=[O:18])(=[O:11])[CH3:8]
Reactant: Cc1cc2c(cc1F)=NC(=O)CCC=2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(F)c(C)cc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 1.0 g of 3,4-dihydro-8-fluoro-7-methyl-2-oxo-1- benzazepine, 15 ml of methanol and 0.7 ml of concentrated hydrochloric acid were added and they were heated under reflux for 3 hours. After the completion of the reaction, the reaction mixture was allowed to cool and the solvent was removed under reduced pressure. To the white residue so obtained, 20 ml of methylene chloride were added, followed by the addition of 1.8 ml of triethylamine and then 0.5 ml of acetic anhydride under ice cooling. They were stirred at room temperature for 2.5 hours. After the completion of the reaction, water and a 5% aqueous hydrochloric acid solution were added to the reaction mixture, followed by extraction with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. The solvent was then evaporated. To the residue so obtained, 8 ml of methanol and 5 ml of a 5% aqueous solution of sodium hydroxide were added and the mixture was stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure. To the residue so obtained, a 5% aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was then evaporated. The residue so obtained was recrystallized from ethyl acetate-chloroform, whereby 0.8 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:16]([Cl:19])OC>C(=S)=S.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[C:12]([CH2:16][Cl:19])[CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COCCl
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(OC)c(CCl)c2)CC1
Temperature: 30 °C
Yield: 102.2 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCl (29.1 g, 364 mmol) in CS2 (300 mL) was added TiCl4 (8.30 g, 43.5 mmol) at 5° C. The reaction mixture was heated at 30° C. for 1 d and poured into ice-water. The mixture was extracted with CH2Cl2 (150 mL×3). The combined organic extracts were evaporated under vacuum to give 1-(3-chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH:8]=[CH:7]2.[CH3:15]I.O>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH3:15])[CH:8]=[CH:7]2
Reactant: CI
Reactant: O=c1[nH]ccc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Sodium hydride (60% in mineral oil) (211 mg, 5.27 mmol) was added to 6-fluoro-1,2-dihydroisoquinolin-1-one (716 mg, 4.39 mmol) in anhydrous DMF (6 mL) cooled in an ice bath. The mixture was stirred for about 30 min at room temperature and methyl iodide (0.328 mL, 5.27 mmol) was added dropwise. After 1 h, the reaction was judged to be about 60% complete and additional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 h, ice and water and ethyl acetate were added to the mixture. After extractive work up with ethyl acetate, the title compound (836 mg) was obtained as a cream solid and carried on without purification.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O1CCCC1.O>[F:28][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[N:11]([S:32]([CH3:31])(=[O:34])=[O:33])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
4-(1-(3-(Difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 30 mg, 0.74 mmol) in tetrahydrofuran (3.0 mL). After 10 min methanesulfonyl chloride (42 μL, 0.55 mmol) is added and the mixture is heated at 50° C. over night. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 74 mg; ESI mass spectrum [M+H]+=458; Retention time HPLC: 0.76 min (005_CA01).
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[C:18]([CH2:31][C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[S:17][C:16]2=[O:41])C=CC=CC=1.O>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:33]#[C:32][CH2:31][C:18]2([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[S:17][C:16](=[O:41])[NH:15][C:19]2=[O:20])=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Trifluoroacetic acid (0.32 mL, 4.07 mmol) was added to a room temperature, stirred suspension of N-(triphenylmethyl)-5-[3-(4-chlorophenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [(X), from Example 35, 1.29 g, 1.94 mmol] in CH2Cl2 (2 mL). Dissolution occurred immediately. After 1 h, the reaction mixture was added to water (200 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate phase was washed with water and brine and then concentrated. The crude product was purified by flash chromatography (95:5 CH2Cl2 :isopropanol) and then triturated in petroleum ether to provide the title compound as a off-white solid (0.52 g, 64%): mp 172°-174° C.; NMR (CDCl3): δ8.00 (s, 1H, NH) 7.85 (d, J=8.3 Hz, 2H, ArH), 7.41 (d, J=8.3 Hz, 2H, ArH), 7.26 (s, 4H, Ar'H), 3.65 (d, J=17.1 Hz, 1H, CH2), 3.33 (d, J=17.1 Hz, 1H, CH2), 2.49 (s, 3H, CH3); MS(CI); 420 (M+H, 58%), 422 (M+H, 24%), 265 (40%), 267 (26%),157 (100%); Anal. Calc. for C19H14ClNO4S2 : C, 54.35; H, 3.36; N, 3.36; Found: C, 54.74; H, 3.54; N, 2.98.
Reaction SMILES: C1C=CN=CC=1.[FH:7].S(F)(=O)(=O)O.O[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:7][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C)(C)O
Reactant: F
Agent: O=S(=O)(O)F
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)F
Temperature: 0 °C
Yield: 52 %

Procedure:
Into a 50-ml autoclave having a teflon-made internal cylinder were placed 9 ml of a hydrogen fluoride/pyridine mixture [hydrogen fluoride/pyridne =70/30 (wt/wt), containing about 300 mM of hydrogen fluoride] and 9.15 g (91.5 mM) of fluorosulfuric acid. The autoclave contents were cooled to 0° C. Thereto was added 4.0 g (30.5 mM) of ethyl 2-hydroxyisobutyrate. The resulting mixture was subjected to a reaction at 40° C. for 4 hours. After the completion of the reaction, the reaction mixture was poured into ice water. The resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove methylene chloride. The resulting residue was subjected to distillation to obtain 2.1 g (yield: 52%) of ethyl 2-fluoroisobutyrate having a boiling point of 124°-126° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([C:17]2[C:22]([CH2:23][CH3:24])=[N:21][C:20]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH2:31][CH3:32])[N:18]=2)=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.CN(C=O)C.C([SiH](CC)CC)C>C(OCC)(=O)C.O.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1>[CH2:31]([C:19]1[C:20]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([C:16]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[N:18]=1)[CH3:32]
Reactant: CCc1nc(-c2cc3c(cc2OS(=O)(=O)C(F)(F)F)CCCC3)c(CC)nc1NC(CC)CC
Agent: CC[SiH](CC)CC
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccc3c(c2)CCCC3)c(CC)nc1NC(CC)CC
Temperature: 60 °C
Yield: 75.4 %

Procedure:
A 7 mL oven dried vial was charged with 3-{3,6-diethyl-5-[(1-ethylpropyl)amino]pyrazin-2-yl}-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (100 mg 0.2 mmol), 1,3-diphenylphosphinopropane (1.65 mg, 0.004 mmol), Pd(AcO)2 (0.9 mg, 0.004 mmol), and DMF (0.5 mL). The reaction was heated to 60° C. on the orbital shaker. Triethyl silane (0.08 mL, 0.5 mmol) was added at once. A color change from yellow to dark orange was observed. The vial was re-sealed with a teflon lined cap and heated to 60° C. for 2 hours. After cooling to ambient temperature, the reaction was diluted with ethyl acetate, poured in H2O, washed once with sat. aq. NaHCO3 and once with Brine. The organic layer was dried with Na2SO4, filtered and concentrated to 120 mg of a crude oil. The crude was purified by Biotage MPLC (40 g column, toluene) to give 53 mg (76%) of 3,6-diethyl-N-(1-ethylpropyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-amine as a clear oil. Rf 0.18 (toluene). IR (liq.) 2964, 2933, 2874, 2858, 2837, 1558, 1508, 1483, 1463, 1444, 1392, 1381, 1212, 1173, 833 cm−1. OAMS supporting ions at: ESI+352.2. Anal. Calcd for C23H33N3: C, 78.58; H, 9.46; N, 11.95. Found: C, 78.20; H, 9.25; N, 11.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:15]>C(Cl)Cl>[Br:15][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: OCc1ccc2cc(F)ccc2c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1ccc2cc(CBr)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution of (6-fluoro-naphthalen-2-yl)-methanol (2.0 g, 11.3 mmol) in CH2Cl2 (30 mL) was added PBr3 (1.0 M in CH2Cl2, 22.6 mmol). The reaction mixture was stirred for 3 h at room temperature before being quenched by NH4Cl (30 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford 2-bromomethyl-6-fluoro-naphthalene (2.23 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.C(=O)(O)[O-:25].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2([OH:25])[CH2:11][CH2:12][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:14][CH2:15]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C([O-])O
Reactant: COc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1F
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(O)(c2ccc(O)c(F)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-(3-Fluoro-4-methoxy-phenyl)-1-methanesulfonyl-1,2,3,6-tetrahydro-pyridine (1.12 g, 3.93 mmol) is dissolved in dry dichloromethane (20 mL) under nitrogen. The solution is cooled to −78° C. and boron tribromide (11.52 g, 7.85 mL, 7.85 mmol) is added by syringe. The reaction is warmed to room temperature and stirred for 1 h followed by the addition of 5% aqueous sodium bicarbonate and dichloromethane. An insoluble solid is formed and filtered to provide 729 mg of the title compound as a pink solid. 1H NMR (CDCl3) δ (ppm): 7.21 (dd, 1H), 7.09 (m, 1H), 6.89 (t, 1H), 3.30 (m, 2H), 3.18 (td, 2H), 2.88 (m, 3H), 2.06 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[CH:64][C:63]([C:66]4[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=4)[C:69](O)=[O:70])=[CH:62][C:56]=3[C:57]=2[C:58](=[O:61])[NH:59][CH3:60])=[CH:49][CH:48]=1>CN(C=O)C>[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[CH:64][C:63]([C:66]4[CH:74]=[CH:73][CH:72]=[C:68]([C:69](=[O:70])[NH:12][C:9]([C:6]5[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=5)([CH3:11])[CH3:10])[CH:67]=4)=[CH:62][C:56]=3[C:57]=2[C:58]([NH:59][CH3:60])=[O:61])=[CH:49][CH:48]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(N)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccncc4)c3)cc12
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-(pyridin-4-yl)propan-2-amine dihydrochloride (26 mg, 0.123 mmol) was added to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol), and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1 hour. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 27%). 1H NMR (500 MHz, DMSO-d6) d ppm 8.73 (1H, s), 8.50-8.55 (1H, m), 8.48 (2H, dd, J=4.58, 1.53 Hz), 8.16 (1H, s), 7.97-8.04 (2H, m), 7.91-7.94 (1H, m), 7.88 (1H, d, J=7.63 Hz), 7.85 (1H, d, J=7.93 Hz), 7.75-7.82 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.36-7.43 (4H, m), 2.86 (3H, d, J=4.58 Hz), 1.68 (6H, s). LC-MS retention time: 1.59 min; m/z (MH+): 508. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=8.60 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=9.26 min, purity=96%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH:29]OS([O-])=O.[K+]>>[Cl:1][C:2]1[C:3]([S:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:29])=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Sc3ccc(Cl)cc3)cc2OC1C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(S(=O)c3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
Following a procedure similar to that described in Example 128, ethyl 6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 192) was treated with OXONE® yielding the products labeled Example 193 and Example 194: mp 213.8-217.4° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.83 (d, 2H, J=8.7 Hz), 7.62 (m, 4H), 5.98 (q, 1H, J=6.8 Hz). 19F NMR (acetone-d6/282 MHz)−79.3 (d, J=7.2 Hz) ESLRMS m/z 435 (M−H). ESHRMS m/z 434.9470 (M−H, Calc'd 434.9472). Anal. Calc'd for C17H9Cl2F3O4S: C, 46.70; H, 2.07; Cl, 16.22; S, 7.33. Found: C, 46.80; H, 2.28; Cl, 16.75; S, 7.39.
Reaction SMILES: [C:1]1([S:7]([CH:9]([P:44]([OH:47])([OH:46])=[O:45])[CH2:10][CH:11]2[O:15][CH:14]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][CH:19]=[N:20][C:21]=4[NH:25]C(=O)C3C=CC=CC=3)[CH:13]([O:34]C(=O)C3C=CC=CC=3)[CH:12]2[F:43])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1NC(=O)C2N=CN([C@@H]3O[C@H](CC(P(=O)(O)O)SC4C=CC=CC=4)[C@@H](F)[C@H]3O)C=2N=1>>[NH2:25][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[C:22]=1[N:23]=[CH:24][N:16]2[CH:14]1[O:15][CH:11]([CH2:10][CH:9]([P:44](=[O:45])([OH:46])[OH:47])[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH:12]([F:43])[CH:13]1[OH:34]
Reactant: O=C(Nc1ncnc2c1ncn2C1OC(CC(S(=O)c2ccccc2)P(=O)(O)O)C(F)C1OC(=O)c1ccccc1)c1ccccc1
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2C1OC(CC(S(=O)c2ccccc2)P(=O)(O)O)C(F)C1O
Yield: 112 %

Procedure:
Compound 49.4 (190 mg, 100% yield) was synthesized from compound 49.3 (247 mg, 0.36 mmol) using the same procedure described for the preparation of compound 35.17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Ic1c[nH]cn1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.45) (1.5 g, 5.4 mmol) and commercially available 4-iodo-imidazole (1.58 g, 8.15 mmol) according to the general procedure IVa. Obtained as a white solid (2.23 g, 95%). MS (ISP) 435.0 [(M+H)+]; mp 235° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([C:31]3[NH:39][C:38]4[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=4[CH:32]=3)[CH:25]=[CH:26][CH:27]=2)[N:22]=1>>[CH2:11]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([C:31]3[NH:39][C:38]4[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=4[CH:32]=3)[CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:12]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CCNc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCN(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
NaHMDS (1.0 M solution in THF; 1.975 ml, 1.975 mmol) was added to N-ethylaniline (0.249 ml, 1.975 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.084 g, 0.282 mmol). The dark red reaction was stirred rapidly at RT. After 2 h, the reaction was quenched with saturated aq. NH4Cl. The reaction was partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The combined organic layers were then the aq. layer was extracted 3×DCM, the combined organics layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(ethyl(phenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.044 g, 0.115 mmol, 40.8% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07-12.29 (1H, m), 7.92-8.19 (2H, m), 7.48-7.63 (3H, m), 7.34-7.47 (3H, m), 7.26 (1H, t, J=7.6 Hz), 6.98-7.07 (1H, m), 6.89-6.98 (1H, m), 6.83 (1H, d, J=9.2 Hz), 4.08 (2H, q, J=7.0 Hz), 3.36-3.44 (2H, m), 2.69 (2H, t, J=6.9 Hz), 1.30 (3H, t, J=7.0 Hz). m/z (ESI, +ve) 383.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)=[O:26])=[C:20]([C:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])(C)(C)C.CCO.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl.C(O)CC>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH2:7][C:8]([CH3:41])([CH3:40])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=3)=[O:26])=[C:20]([C:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=3)[CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: CC(C)(N)CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of [3-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-1,1-dimethyl-3-oxo-propyl]-carbamic acid tert-butyl ester (33.0 mg, 0.0574 mmol) (as prepared in the previous step) in 3 mL of DCM and 0.10 mL EtOH at 0° C. was added 1.0 mL of TFA, the mixture was warmed to RT and stirred for 3 h. The reaction was diluted with 3 mL of n-PrOH and then concentrated in vacuo. The residue was purified by flash chomatography (silica gel, 3-8% MeOH/DCM) to give 33.5 mg (99%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3): δ 13.3 (s, 1H), 9.52 (s, 1H), 8.57 (br s, 3H), 8.26 (d, 1H, J=8.6 Hz), 7.69 (s, 1H), 7.02 (dd, 1H, J=8.6, 1.7 Hz), 6.98 (d, 1H, J=1.7 Hz), 5.78 (m, 1H), 4.67 (br d, 1H, J=13.4 Hz), 3.88 (br d, 1H, J=13.4 Hz), 3.10 (m, 1H), 2.55-2.85 (m, 4H), 2.23 (m, 4H), 1.72-2.01 (m, 8H), 1.50 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H34N6O2, 475.3 (M+H), found 475.1.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)#[N:2].Br[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:22]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][NH:12][C:4]([NH:3][C:1]#[N:2])=[N:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:20][CH2:19]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#CNC(=Nc1ccncc1)NCCN1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#CNC(=Nc1ccncc1)NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 50 %

Procedure:
N-cyano-N′-(2-piperazin-1-yl-ethyl)-N″-pyridin-4-yl-guanidine (273 mg, 1 mmol) (prepared using the procedure described in Example 7) and bromodiphenylmethane (247 mg, 1 mmol) was dissolved in dimethylformamide (1.5 mL), followed by the addition of triethylamine (0.21 mL, 1.5 mmol). The reaction solution was stirred at room temperature under nitrogen for 10-15 hours and then diluted with 100 mL ethyl acetate. The organic layer was washed with water (3×30 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give crude title product. The final product was further purified by flash column chromatography (SiO2, 10% MeOH in EtOAc). The pure product was obtained in 50% yield in two steps. 1H-NMR (CD3OD, ppm): 8.36 (d, 2H), 7.18-7.43 (m, 12H), 4.29 (s, 1H), 3.46 (t, 2H), 2.45-2.61 (m, 10H). ESMS 440.4 (M+1), 462.4 (M+23).