Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH2:15].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH:15][C:24](=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])cc(F)c1N
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1c(F)cc([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
To a solution of 2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH2Cl2 (30 mL) was added and butyryl chloride (1.8 g, 17 mmol) dropwise at 0° C. After stirring for 5 h at 0° C., the reaction mixture was poured into ice (50 g) and extracted with CH2Cl2 (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give N-[2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 62%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 8.10 (dd, J=1.5, 2.7 Hz, 1H), 7.95 (dd, J=2.4, 9.6 Hz, 1H), 7.22 (brs, 1H), 2.45 (t, J=7.5 Hz, 2H), 1.82 (m, 2H), 1.36 (s, 9H), 1.06 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: ClCCN1CCCC1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(Br)ccc1OCCN1CCCC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 6.00 g (29.85 mmol) of 5-bromo-2-hydroxybenzaldehyde, 5.84 g (3.43 mmol) of 1-(2-chloroethyl)pyrrolidine, and 12.38 g (89.54 mmol) of potassium carbonate was stirred for 2 hours at 50° C. and for 2 hours at 75° C., cooled to RT, filtered, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient EtOAc/MeOH 100:0→85:15). Yield: 5.89 g (66% of theoretical); C13H16BrNO2 (M=298.176); calc.: molpeak (M+H)+: 298/300 (Br); found: molpeak (M+H)+: 298/300 (Br); HPLC-MS: 4.82 minutes (method A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:33]([C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:11]=[CH:10][CH:9]=1)#[C:34][CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCCC#Cc1cccc(CC(=O)OCC)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of ethyl(3-bromophenyl)acetate (0.3 g, 1.24 mmol) and tetrabutylammonium fluoride hydrate (0.97 g, 3.72 mmol), was treated with PdCl2(PPh3)2 (26 mg, 0.037 mmol; 3 mole %) and 1-pentyne (367 μL, 3.72 mmol) in a sealed tube. The tube was heated at 80° C. for 2 h. The mixture was treated with water, and was extracted with diethyl ether. The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product. Purification on a Biotage™ 25 M column (silica), eluting with ethyl acetate/hexane 0:1 to 2:98, gave ethyl (3-(pentyne-1-yl)phenyl)acetate as a pale yellow oil (0.23 g, 79%).
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]([F:9])([F:8])[C:5]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:4]=2[O:3]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([F:16])([F:1])[O:7][C:6]([F:9])([F:8])[C:5]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Product: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1

Procedure:
A mixture of (2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-methanol (6.5 g) in thionyl chloride (75 mL) was heated at reflux overnight. The resulting mixture was concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over Na2SO4, filtrated, and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g), which was used directly in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1 H), 7.61 (dd, J=2.1, 8.7 Hz, 1 H), 7.15 (d, J=8.4 Hz, 1 H), 4.60 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:38]3[CH2:39][CH2:40][N:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:37]3)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 46 h
Yield: 61.9 %

Procedure:
To the suspension of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol), tert-Butyl 1-piperazinecarboxylate (20.8 mg, 0.112 mmol) and Acetic acid (11 mg, 0.18 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) was added Sodium triacetoxyborohydride (27.0 mg, 0.128 mmol). The mixture was stirred at r.t. for 46 hours. The mixture was washed with water (2×2 mL) and brine, dried over Na2SO4, filtered and the filtrate was chromatographed in an 8 g AnaLogix column using MeOH/DCM (0/100 to 5/95) to give a solid product (0.0253 g, 61.9% yield). LCMS: (FA) ES+ 641. 1H NMR (400 MHz, d-chroloform) δ 9.91 (s, 1H), 8.28 (s, 1H), 7.94-7.97 (m, 2H), 7.58-7.60 (m, 1H), 7.34-7.46 (m, 4H), 5.47-5.51 (m, 1H), 4.05-4.13 (m, 1H), 3.70-3.76 (m, 1H), 3.58 (s, 2H), 3.42 (s, br, 4H), 2.81 (s, 3H), 2.45 (s, br, 4H), 2.00-2.17 (m, 3H), 1.65-1.72 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37](Cl)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.24) (135 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (43 mg, 15%). MS (ISN) 587.3 [(M−H)−]; mp 272° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([O:22][CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH2:9][CH2:10][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2cccc(Br)c2)CC1
Product: N#CC1(c2ccccc2)CCC(OCC2CC2)(c2cccc(Br)c2)CC1

Procedure:
The title compound was prepared from 4-(3-bromophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile and bromomethylcyclopropane according to the process described in Example 41.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:6][C:5]=1[F:11]
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(F)nc1F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCc2ccc(Cl)cc2)nc1F
Reaction time: 2 h

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 2.00 g, 0.0116 mol) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., was added p-chlorobenzylamine (61, 2.60 mL, 0.0214 mol). The reaction was stirred at −40° C. to −20° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give compound (62, 2.0 g, 58.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH2:14][CH2:15][O:10][CH2:11][CH2:12]3)=[CH:22][CH:21]=2)[N:7]=[CH:6][N:5]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and 4-morpholinoaniline.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:47])([F:48])[C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of ethyl 10-[(3RS,4RS)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.5 g, 0.67 mmol) in dichloromethane (10 mL) was cooled to −78° C. To this solution, a solution of boron tribromide in dichloromethane (1M, 5.37 ml) was slowly added dropwise, and the resulting mixture was stirred for 1 hour. The reaction vessel was then transferred to an ice-bath and the reaction mixture was further stirred for 3 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.4 g, Yield 84%) as a foam.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30](=[O:51])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48]CO)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30](=[O:51])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:1][Br:5])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOCCBr
Reaction time: 5 h
Yield: 91.9 %

Procedure:
Carbon tetrabromide (9.0 g, 27 mmol) and triphenyl phosphine (1.2 g, 4.5 mmol) were added to a solution of compound 2 (1.8 g, 4.5 mmol) in dry CH2Cl2 (100 mL). After stirring the reaction mixture for 5 h, the solvent was concentrated in vacuo and the residue was loaded onto a silica gel gravity column (200 g) and eluted with CH2Cl2:MeOH 100:0 to 20:1 (v/v) to afford compound 3 as a colorless oil (1.9 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[F:9][C:10]([F:21])([F:20])[C:11]1[C:12](F)=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C1CCCCC1>CN(C=O)C>[F:9][C:10]([F:20])([F:21])[C:11]1[C:12]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Reactant: Nc1ccccc1S
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(F)(F)F)c1Sc1ccccc1N

Procedure:
Using a procedure analagous to that of Example 3(a), 2-aminothiophenol (6.26 g, 50 mmol) was combined with 3-trifluoromethyl-2-fluorobenzonitrile (1 eq) in DMF solvent (50 ml) to give the title compound as a white solid from cyclohexane (10.41 g).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.C(O)(=O)C.C(OCC)C.C(=O)([O-])O.[Na+].[BrH:29]>>[Br:29][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: Br
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 g of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (3.62 mmol, 1 eq.) were dissolved in 1.72 ml of 33% hydrogen bromide in glacial acetic acid (9.97 mmol, 2.75 eq.) and stirred at room temperature for 2 hours. 25 ml of diethyl ether were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was added dropwise to 80 ml of aqueous saturated sodium hydrogen carbonate solution and stirred again at room temperature for 15 min. The separated aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo to yield 991 mg (3.56 mmol, 98.4%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (8 g, 50.5 mmol) and ammonium acetate (9.72 g, 126 mmol) in acetic acid (168 mL) was added nitromethane (8.16 mL, 151 mmol). The reaction mixture was heated at reflux for 5 h and cooled down. Water (100 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was filtered, washed by water, and dried under vacuum. The solid was purified by flash chromatography (0-20% EtOAc/heptane) to yield clean product 4.2 g in 41% yield. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, J=13.7 Hz, 1H), 7.54 (d, J=13.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.33 (dd, J=2.0, 9.3 Hz, 1H), 7.31-7.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: NCCCn1ccnc1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCn2ccnc2)ccc1Cl

Procedure:
Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg) and 1-(3-aminopropyl)imidazole according to the procedure described in Example 6f to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22](N(C2CC2)CC2C=CC(OC)=CC=2)[C:23]2[N:24]([C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[N:25]=1>CO>[Cl:19][C:20]1[CH:21]=[C:22]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:23]2[N:24]([C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[N:25]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COc1ccc(CNCCN2CCOCC2)cc1
Solvent: CO
Product: COc1ccc(CN(CCN2CCOCC2)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
17A was prepared from 1F and N-(4-methoxybenzyl)-2-(4-morpholinyl)ethanamine following the procedure employed in the preparation of 1G. HPLC: Rt=2.95 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=427.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:12]3=[N:16][N:17]=[CH:18][N:11]3[C:10](=[O:19])[NH:9][C:8]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.O>[CH2:26]([N:9]1[C:8]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:15]=[N:14][C:13]=2[C:12]2=[N:16][N:17]=[CH:18][N:11]2[C:10]1=[O:19])[CH:27]([CH3:29])[CH3:28]
Reactant: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n2cnnc2c2ncn(C3CCCCO3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (2.08 g, 4.0 mmol) in DMF (20 ml), was added potassium carbonate (1.10 g, 8.0 mmol) and isobutyl iodide (1.47 g, 8.0 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to give the product. LCMS calculated for C15H21N6O2(M+H): 317.2; found: 317.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[CH2:3][CH2:2]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(NC2CCNCC2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Fc1ccc(CN2CCC(Nc3ccc(C(F)(F)F)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A suspension of D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g, 5.32 mmol), di-isopropylethylamine (1.37 g, 10.6 mmol) and triacetoxyborohydride on resin (Argonaut Technologies; 2.2 mmol/g; 3 eq.) in dichloroethane (10 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was filtered and the solvents evaporated in vacuo. The crude product was purified by chromatography (silica; 2%-6% ammonia in methanol (7 M)/dichloromethane) to give E2 (0.79 g, 42%). C17H18F4N4 requires 354; Found 355 (MH+); mp: 163.3-165.3° C. 1H NMR (DMSO-D6) δ 1.48 (q, J=10.8 Hz, 2H), 1.95 (br.d, J=12.5 Hz, 2H), 2.09 (t, J=11.1 Hz, 2H), 2.78 (br.d, J=11.3 Hz, 2H), 3.47 (s, 2H), 3.89 (br.s, 1H), 6.94 (d, J=9.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.34 (dd, J=8.3, 5.7 Hz, 2H), 7.53 (br.d, J=7.3 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[CH3:16][NH:17][CH:18]([N:21]1[C:27](=[O:28])[CH2:26][C:25]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:24]=2[CH2:23][CH2:22]1)[CH2:19][CH3:20]>>[CH3:16][N:17]([CH:18]([N:21]1[C:27](=[O:28])[CH2:26][C:25]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:24]=2[CH2:23][CH2:22]1)[CH2:19][CH3:20])[CH:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1)[CH3:2]
Reactant: CCC(NC)N1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1ccc2cc(CCBr)ccc2c1
Product: CCC(N1CCc2cc(OC)c(OC)cc2CC1=O)N(C)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 100 °C

Procedure:
A mixture of 0.66 g (2.5 mmol) of 2-(2-bromoethyl)-6-methoxy-naphthalene and 1.46 g (5 mmol) of 3-(N-methyl-amino-prop-3-yl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one is heated to 100° C. for 90 minutes. After cooling, the crude product is purified over 70 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 0.25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:8])=[CH:5][S:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([C:13](=[CH:12][NH:8][C:4]1[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20])[CH3:23]
Reactant: COc1cscc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cscc1OC)C(=O)OCC

Procedure:
4-Methoxy-3-thiopheneamine (11.8 g, 0.091 mol) and diethyl ethoxymethylenemalonate (19.75 g, 0.091 mol) in toluene (300 ml) was heated under reflux in an atmosphere of nitrogen for 18 hours. The solvent was evaporated under reduced pressure to give a buff-coloured solid, this was washed with petroleum ether (b.p. 40°-60°) and the title compound collected by filtration, 25.23 g, m.p. 100°-102°.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:30][C:31]1[C:36]([Pb+3])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][C:31]1[C:36]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C

Procedure:
To a mixture of bicyclo[3.2.1]octane-2,4-dione (0.553 g, 4 mmol) in dry chloroform (12 ml) is added 4-dimethylaminopyridine (2.44 g, 20 mmol), and the mixture is stirred at room temperature until all the solid is dissolved. To this solution is then added dry toluene (8 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 10 ml, 5 mmol), and the mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 3-(3,5-dimethylbiphen-4-yl)bicyclo[3.2.1]octane-2,4-dione as a white powder.