Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:12])[CH:3]=1.[C:13](=[NH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:20]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:26][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([F:12])[CH:3]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)cc2ncccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1cc(N=C(c2ccccc2)c2ccccc2)cc2ncccc12
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 7-bromo-5-fluoroquinoline (128 mg, 0.566 mmol), benzophenone imine (0.143 mL, 0.849 mmol, Aldrich), Pd(dba)2 (32.6 mg, 0.057 mmol, Strem), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (70.5 mg, 0.113 mmol, Aldrich) and sodium 2-methylpropan-2-olate (82 mg, 0.849 mmol, Aldrich) in toluene (4 mL) was stirred at 110° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid, which was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:27][CH:28]1[O:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(Cl)Cl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:30]3[CH2:31][CH2:32][O:33][CH:28]([CH3:27])[CH2:29]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC1CNCCO1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)CCO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.9 %

Procedure:
To polymer N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (0.038 g) in an Alltech™ tube was added a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.007 g) in DCM (0.9 ml) followed by 2-methylmorpholine (0.004 g) in DMF (0.1 ml) and N,N-diisopropylethylamine (0.006 ml). The mixture was shaken at room temperature for 4 days. The tube was drained, the filtrate collected and the resin washed with DCM. The combined DCM solutions were concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.0038 g) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O>>[CH3:19][C:5]1[N:4]([CH2:3][CH:2]([O:1][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:20])[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Reactant: Oc1ccccn1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1ccccn1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 2-pyridinol: MS (ES) m/z 360 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]([NH:8][C:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:15])[CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:26])=[O:25]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (1.6 g, 7.36 mmol) in dichloromethane (15 mL) was added triethyl amine (2.052 mL, 14.73 mmol) at 0° C. and the solution was stirred for 5 min. To this mixture at 0° C. was added methanesulfonyl chloride (0.574 mL, 7.36 mmol) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated under reduced pressure to yield (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 5.75 mmol, 78% yield) as a yellow solid which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 1H), 4.25 (m, 1H), 4.16 (m, 1H), 3.92 (m, 1H), 3.05 (s, 3H), 1.66 (m, 2H), 1.56 (m, 10H), 0.92 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a stirred solution of 4-nitrobenzeneethanol (3.34 g, 20.0 mmol) and triethylenediamine (3.36 g, 30.0 mmol) in DCM (62.7 mL) at 0° C. was added 4-nitrobenzenesulfonyl chloride (4.97 g, 22.43 mmol) in portions over a 5 min period. The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was added and the resulting mixture was stirred for 10 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (5.8 g, 82% yield) as a yellow solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:23])[CH3:22])[S:19][CH:20]=2)[CH:14]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([C:21](=[O:23])[CH3:22])[S:19][CH:20]=2)[CH:14]=1
Reactant: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {1-[2-(1-hydroxy-ethyl)-thiazol-4-ylmethyl]-1H-pyrazol-4-yl}-carbamic acid 2-chloro-benzyl ester in AcCN (1.0 mL) was treated at rt with MnO2 (49.2 mg, 0.51 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite to give the title compound as a brown foam. LC-MS-conditions 02: tR=0.98 min; [M+H]+=390.98.
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[O:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[C:35]4[CH2:36][CH2:37][O:32][CH2:33][CH:34]=4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3C3=CCOCC3)nc2N1C1CCCC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 130 mg, 1 eq) in dioxane/water/MeOH (2 mL/0.5 mL/0.05 mL) was combined with Pd(dppf)Cl2 (39.6 mg, 0.2 eq), Na2CO3 (100 mg, 3 eq), and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (116 mg, 2 eq). The reaction mixture was stirred at 110° C. overnight. This was diluted with EtOAc and a saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC and further purified by preparative HPLC. LCMS: 409.2 m/z (M+H)+; ret. Time: 2.41 min (Analytical Method A). 1H-NMR (CDCl3, 300 MHz): δ: 7.81 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 6.51 (s, 1H), 4.35-4.30 (m, 4H), 3.90-3.81 (m, 4H), 3.40 (s, 3H), 2.41-2.3 (m, 1H), 2.20-1.54 (m, 9H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: COC(=O)[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH:16]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[C:9]=1[F:38].[OH-].[Na+]>O.C(O)(=O)C.O1CCCC1.CO>[F:38][C:9]1[C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][C:12]([O:14][CH3:15])=[CH:11][C:10]=1[CH:16]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=1)[C:17]1[NH:21][C:20](=[O:22])[N:19]([C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)[N:18]=1
Reactant: COC(=O)OCCOc1cc(OC)cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a mixture of the crude product of carbonic acid 2-{3-[(4-cyanophenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester methyl ester (2.02 g), methanol (6 mL), tetrahydrofuran (6 mL), and water (2.3 mL), 5 N aqueous sodium hydroxide solution (3.71 mL, 18.6 mmol) was added. Methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL) were added to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours and 30 minutes. Acetic acid (4.25 mL) was added to the reaction solution, and the resulting mixture was stirred for 20 minutes, after which water (20 mL) was added dropwise thereto, and the resulting mixture was stirred at room temperature for 1 day. The precipitated solid was filtered and washed with water (6 mL) and tert-butyl methyl ether (6 mL). The solid obtained was dried under air flow to obtain the captioned compound (1.576 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([N+:18]([O-])=O)[C:11]=2[N:10]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=2[N:10]=1
Reactant: COc1ccccc1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1nc2c(N)cccc2[nH]1
Yield: 95.2 %

Procedure:
A suspension of 163 (0.620 g, 2.303 mmol), ammonium chloride (0.105 g, 1.957 mmol) and iron (0.643 g, 11.51 mmol) in ethanol (20 ml) and water (4.00 ml) was heated at reflux for 2 hours. The reaction mixture was cooled and filtered through Celite and the filtrate was taken to dryness, H20 was added and the material extracted with ethyl acetate. The EtOAc extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give crude 164 (0.5245 g, 2.192 mmol, 95% yield) as brown solid. LRMS (ESI): (calc.) 239.3 (found) 240.2 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Na].[Cl:10][CH2:11][CH2:12][CH2:13]I>O1CCCC1>[CH2:3]([S:8][CH2:13][CH2:12][CH2:11][Cl:10])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClCCCI
Reactant: CCCCCS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSCCCCl
Temperature: -78 °C
Yield: 59 %

Procedure:
A suspension of sodium hydride (4.0 g, 100 mmole) in dry tetrahydrofuran (350 mL) under a nitrogen atmosphere was cooled in an ice bath. Pentyl mercaptan (10.8 g, 100 mmole) was added dropwise over 10 minutes. The resulting suspension of sodium alkylmercaptide was added in portions over 30 minutes to a stirred solution of 1-chloro-3-iodopropane (20.44 g, 100 mmole) in tetrahydrofuran (450 mL) that had been cooled to -78° C. The mixture was allowed to warm to ambient temperature overnight, then washed with brine, dried over MgSO4, and concentrated under vacuum. The resultant oil was distilled under water aspirator pressure to yield the desired product (10.67 g, 59% yield), b.p. 113°-119° C. (20 mm Hg).
Reaction SMILES: BrC1C=CC=[C:6]2[C:11]=1[N:10]=[C:9](C1C=CC=C(F)C=1)[C:8](CN1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7]2.ClC1C(C=O)=CC2C(=C(Cl)C=CC=2)N=1.[Cl:45][C:46]1[C:55]([CH2:56][N:57]2[C:65](=[O:66])[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:58]2=[O:67])=[CH:54][C:53]2[C:48](=[C:49]([Cl:68])[CH:50]=[CH:51][CH:52]=2)[N:47]=1.[Br-].N1C=CC=CC=1[Zn+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:45][C:46]1[C:55]([CH2:56][N:57]2[C:65](=[O:66])[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C:58]2=[O:67])=[CH:54][C:53]2[C:48](=[C:49]([Cl:68])[CH:50]=[CH:51][CH:52]=2)[N:47]=1.[Cl:68][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:48]=1[N:47]=[C:46]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:11][N:10]=1)[C:55]([CH2:56][NH2:57])=[CH:54]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cccc(Br)c2nc1-c1cccc(F)c1
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)N1Cc1cc2cccc(Cl)c2nc1Cl
Agent: O=Cc1cc2cccc(Cl)c2nc1Cl
Solvent: C1COCCO1
Product: NCc1cc2cccc(Cl)c2nc1-c1ccccn1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
2-((2,8-Dichloroquinolin-3-yl)methyl)isoindoline-1,3-dione was prepared in the similar manner as 2-((8-bromo-2-(3-fluorophenyl)quinolin-3-yl)methyl)-isoindoline-1,3-dione from 2,8-dichloroquinoline-3-carbaldehyde. A mixture of 2-((2,8-dichloroquinolin-3-yl)methyl)isoindoline-1,3-dione (71 mg, 0.2 mmol), 2-pyridylzinc bromide (0.5 M, 0.8 mL, 2.0 eq) and tetrakis(triphenylphosphine) palladium (11 mg, 5%) in dioxane (3 mL) was purged with N2 and heated to 65° C. After 12 h, the reaction was cooled to rt and quenched with NH4Cl solution. After work up, The residue containing a mixture of 2-((8-chloro-2-(pyridin-2-yl)-quinolin-3-yl)methyl)isoindoline-1,3-dione and 2-(((8-chloro-2-(pyridin-2-yl)-quinolin-3-yl)methyl)carbamoyl)benzoic acid was treated with NH2NH2 (31 μL) in EtOH (1 mL) at reflux. After usual work up, the residue was purified on column chromatography on silica gel (DCM/MeOH/Et3N, 20/1/0.1) to give a pale yellow solid as (8-chloro-2-(pyridin-2-yl)quinolin-3-yl)methanamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (d, J=8.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.13 (s, 3H). Mass Spectrum (ESI) m/e=270 (M+1).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]([C:18](O)=[O:19])=[CH:16][C:15]2[S:21][CH:22]=[CH:23][C:14]1=2.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:18]([C:17]3[S:13][C:14]4[CH:23]=[CH:22][S:21][C:15]=4[CH:16]=3)=[O:19])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2sccc2s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2sccc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[3,2-b]thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.71 (d, J=5.1 Hz, 1H), 8.12 (s, 1H). MS (DCI/NH3) m/z 319.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)C.C(N)=N>COCCO>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[CH:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: COCCO
Product: c1ccc(-n2cnc3ccccc32)cc1

Procedure:
To a flask were added crude N-phenylbenzene-1,2-diamine, 9.7 g formamidine acetate and 175 ml 2-methoxyethanol and the mixture was heated to reflux under nitrogen for 30 minutes. After cooling to 22 C, the solvent was removed and the mixture was dissolved in ethyl acetate and washed with water. Following removal of the solvent, the product was purified by silica gel chromatography using 50% ethyl acetate in hexane giving a tan oil.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[N:16]3)[S:12][CH:13]=2)OCC[O:5]1.Cl.[OH-].[Na+]>C1COCC1.O>[N+:20]([C:17]1[CH:18]=[CH:19][N:15]([CH2:14][C:11]2[S:12][CH:13]=[C:9]([C:4](=[O:5])[CH3:3])[N:10]=2)[N:16]=1)([O-:22])=[O:21]
Reactant: CC1(c2csc(Cn3ccc([N+](=O)[O-])n3)n2)OCCO1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1csc(Cn2ccc([N+](=O)[O-])n2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(2-methyl-[1,3]dioxolan-2-yl)-2-(3-nitro-pyrazol-1-ylmethyl)-thiazole (250 mg, 0.84 mmol) in THF (10.0 mL) was treated at 0° C. with HCl (2.5 mL of a 1M solution in water, 2.50 mmol). The reaction mixture was stirred at rt for 6 h. Water (10 mL) was added and the aqueous layer was set to pH 9-10 using 1M NaOH. The aq. layer was extracted with EA (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow solid. TLC: rf (19:1 CH2Cl2-MeOH)=0.25. LC-MS-conditions 02: tR=0.81 min; [M+H]+=253.06.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:13]=1[C:14]#[N:15]>>[F:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1cc(O)ccc1F
Product: N#Cc1cc(Oc2ccc(C=O)cc2F)ccc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde (188 mg, 1.32 mmol) and 2-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:14]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a stirred solution of 2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.737 g, 3.4 mmol) in dry CH2Cl2 (10 mL) was added 3 Å molecular sieves (1.03 g), N-methylmorpholine N-oxide (0.644 g, 5.5 mmol), and tetrapropylammonium perruthenate (72 mg, 0.21 mmol) and the mixture stirred at room temperature for 3 h. The reaction mixture was purified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by 100:0) to afford the title aldehyde (0.500 g, 70%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:24])[CH3:2]
Reactant: CCSCC1CCCCc2noc(=O)n21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)CC1CCCCc2noc(=O)n21

Procedure:
The product of Example 38 is reacted with one equivalent of MCPBA in CH2Cl2 to generate the title material.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[N:37]=1>O1CCCC1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([N:38]=[C:39]([CH3:41])[N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc2ccc(Cl)nn2n1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinepropanol (743 mg) was dissolved in dried tetrahydrofuran (17 ml), followed by addition of sodium t-butoxide (241 mg). The mixture was heated to 60° C. and stirred for 30 minutes. After the mixture was cooled, 6-chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine (384 mg) was added thereto, followed by reflux under heating for 21 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (50:5:1). Fractions containing the objective compound were collected. The resulting crystals were washed with ethyl ether and dried to yield the title compound (700 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].O>CO>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:13](=[O:14])[C:12]([F:18])([F:17])[F:11])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COC(=O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
10 mmol of 3′-aminoacetophenone as a starting material was dissolved in a methanol solvent in a 100 mL round-bottomed flask and 1.2 equivalents (eq) of methyl trifluoroacetate was added dropwise thereto over 30 minutes at room temperature, and subsequently the reaction mixture was stirred for 2 hours. After the completion of the reaction was confirmed by TLC, a small amount of water was added to terminate the reaction. Then, the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and washed twice with 30 mL of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the desired 3-acetyl-trifluoroacetylaminobenzene (85%) as a brown oil.