Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[Cl-].[NH4+]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 89 %

Procedure:
Sodium hydride (60% oil dispersion, 4.00 g, 100 mmol) was added to a dry 500 ml flask under nitrogen and washed with three 25 ml portions of hexanes. Anhydrous DMSO (100 ml) was added, followed by dimethyl malonate (11.4 ml, 100 mmol). The reaction was heated briefly to 100° C. with stirring, then cooled to room temperature. 2,5-Dibromonitrobenzene (12.9 g, 46.0 mmol) was added and the reaction was heated at 110° C. for 2 hrs. After cooling to room temperature, the solution was added in portions to 300 ml of saturated aqueous ammonium chloride with 150 ml of 1:1 hexanes/ethyl acetate. The organic layer was washed with 300 ml of saturated aqueous ammonium chloride, four 200 ml portions of water, and 200 ml of saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give 13.6 g of crude dimethyl 2-(4-bromo-2-nitrophenyl)malonate as a brown oil. This material (30-40 mmol) was heated to 110° C. in 250 ml DMSO with 3.6 g (84 mmol) of lithium chloride and 750 mg (42 mmol) of water for 4.5 hrs. The reaction was cooled to room temperature and added to 300 ml of ethyl acetate with 300 ml of saturated aqueous sodium chloride. The organic layer was washed with a second portion of 300 ml saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was removed to give 11.1 g brown oil. This material was adsorbed on 40 g of silica gel and applied to a column containing another 80 g of silica gel. Elution with 0-10% ethyl acetate in hexanes gave 3.53 g (28% from 2,5-dibromonitrobenzene) of methyl (4-bromo-2-nitrophenyl) acetate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.BrN1C(=[O:19])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)C>C(Cl)(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH:1]=[O:19])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncco2)cc1
Agent: [Ag+]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ncco2)cc1
Temperature: 100 °C

Procedure:
To 2-(4-methylphenyl)oxazole (6.41 g, 40.3 mmol) and N-bromosuccinimide (14.7 g, 82.6 mmol) in carbon tetrachloride (300 mL) was added 2,2′-azobisisobutyronitrile (500 mg, 3.1 mmol) and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was cooled to 0° C., filtered through a fritted funnel, and concentrated in vacuo. To this crude reaction mixture was added 95% ethanol (300 mL) and silver nitrate (15.1 g, 88.8 mmol), and the reaction mixture was refluxed for 4 h, cooled to room temperature, filtered through a fritted funnel, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 10:1 hexanes/ethyl acetate) gave 880 mg (13%, 2 steps) of the title compound. MS 174 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]([C:18](=O)[C:19]([OH:21])=[O:20])[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(O)COCCO.O.NN.[OH-].[K+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([OH:21])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC1=CN2C(=NC(c3ccc(C)cc3)C2C(=O)C(=O)O)C=C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: OCCOCCO
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a clean round bottom flask was charged oxoacetic acid (68 mmol) from example 1, 100 ml of diethylene glycol, hydrazine hydrate (184 mmol) and potassium hydroxide (115 mmol). The reaction mixture was heated to a temperature of 120-180° C. The reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and 100 ml of water was added. The reaction mass was further cooled to 0-10° C. and the pH was adjusted to 6-6.5 using acetic acid and stirred for 1 hour. The solid obtained was filtered, washed with water and dried in oven at 90-100° C. Yield: 16 gm of the title compound, m.p. 228-230° C. Purity 97% (HPLC).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13]Cl)[O:6][CH2:5][CH2:4][O:3]1.[C-:15]#[N:16].[Na+].[Na+].[I-].[C-]#N.[K+]>CCO.O>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:15]#[N:16])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCC#CCCCCl)OCCO1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(CCC#CCCCC#N)OCCO1
Yield: 96.5 %

Procedure:
2-Methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane (21.6 g, 0.1 mol) was dissolved in 120 ml EtOH (convenience; dimethylformamide, dimethylsulfoxide, or other polar solvents may be used) and added to a solution of NaCN (9.8 g, 0.2 mol) and NaI (2.0 g, 0.013 mol) in 80 ml H2O. KCN, NH4CN or other cyanide salts may be used. The reaction was concentrated to remove the solvent and was extracted with three 100 ml portions of ether. The combined organic extracts were washed with 2-50 ml portions of water and brine. After drying over anhydrous MgSO4, the solvent was removed to give 20 g of 2-methyl-2-(7-cyano-3-heptynyl)-1,3-dioxolane, pure enough to use directly in the next step. Yield: 20 g, 99%. IR (CHCl3): 3000, 2950, 2890, 2250, 1675 cm-1.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:6]2[CH2:7][N:8]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.270 g (1.692 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.36 g (1.9 mmol) of 6-phenylhexanoic acid and 0.94 ml (6.8 mmol) of triethylamine in 30 ml of dichloromethane, 0.39 ml (2.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[O-:16][C:17]#N.[K+]>O>[Cl:9][C:7]1[C:6]([Cl:10])=[CH:5][C:4]2[N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:17](=[O:16])[NH:2][C:3]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCO
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred mixture of 31.2 parts of 3[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minutes-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15 and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48%) of 5,6-dichloro-1,3-dihydro-1(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethyl-ethanamine and 260 parts of dichloromethane are added dropwise 7.4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux temperature. The reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].C=CC1C=CC=CC=1.C=CC(O)=O.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.Cl.N1C=CC=CC=1>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].[C:15]([O:19][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][O:33]1)(=[O:18])[CH:16]=[CH2:17]
Reactant: C1=COCCC1
Reactant: C=CC(=O)O
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: C=CC(=O)OC
Product: C=CC(=O)OC1CCCCO1

Procedure:
Using the procedure of Example 6, reaction of 10 g of poly(styrene [55 wt %], methyl acrylate [20 wt %], acrylic acid [25 wt %]) (Joncryl 67), 125 mL of 3,4-dihydro-2H-pyran, and 0.1 g of pyridine hydrochloride gave 10 g of poly(styrene, methyl acrylate, tetrahydropyranyl acrylate) after precipitation from dichloromethane in methanol at -70° C. 1H NMR (360 MHz, THF-d8): 5.9 (OCHO of tetrahydropyranyl ester). Mole ratio of styrene to tetrahydropyranyl ester=1.8:1. GPC: Mn=6260, Mw=15,900, Mw/Mn=2.54. DSC: Tg=52° C., decomposition endotherm peak at 180.77° C. (125.4 J/g). TGA: 20.69% weight loss at about 180° C. Titration of the product with 0.1N sodium hydroxide shows the presence of 0.2 meq/g of residual carboxylic acid groups. Titration of the starting material shows 3.4 meq/g of carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:51][N:52](C)[CH2:53]CO>O>[CH3:51][N:52]([CH3:53])[CH2:2][CH2:1][O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:31])=[O:32])=[CH:6][N:5]=1
Reactant: CN(C)CCO
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCN(C)C)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of the title compound of Example 26 (200 mg, 0.35 mmol), potassium bis(trimethylsilyl)amide (352 mg, 1.76 mmol) and 2-dimethylaminoethanol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. Water (5 ml) was added, the mixture extracted with ethyl acetate (3×5 ml) and the combined extracts dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (95:5 to 90:10), to give the title compound (147 mg, 68%) as an off-white foam. Found: C, 56.35; H, 6.37; N, 20.12. C29H39N9O4S; 0.50 H2O requires C, 56.29; H, 6.52; N, 20.37%. δ (CDCl3): 0.94 (3H,t), 1.04 (3H,t), 1.72 (2H,m), 2.43 (8H,m), 2.56 (4H,m), 2.74 (2H,t), 2.95 (2H,t), 3.15 (4H,m), 4.80 (2H,t), 5.67 (2H,s), 7.07 (1H,d), 7.21 (1H,m), 7.61 (1H,m), 8.56 (1H,d), 8.62 (1H,s), 8.75 (1H,s), 12.23 (1H,s). LRMS: m/z 610 (M+1)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:22])([F:21])[C:15]([CH3:20])=[CH:16][C:17](O)=[O:18].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>C1COCC1.O>[F:13][C:14]([F:22])([F:21])[C:15]1[CH:20]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)[NH:30][C:17](=[O:18])[CH:16]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CC(=CC(=O)O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CSc1ccc(-c2cc(C(F)(F)F)cc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To a stirred solution of diisopropylamine (11.5 mL, 81.8 mmol) in THF (75 mL) at 0° C. was added n-butyllithium (51.1 mL of a 1.6M solution in hexanes, 81.8 mmol). After stirring for 15 minutes, a solution of 4,4,4-trifluoro-3-methyl-2-butenoic acid (6.0 g, 38.9 mmol) in THF (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 30 minutes before being cooled to 0° C. and treated dropwise with a solution of 4-(methylthio)benzonitrile (2.91 g, 19.5 mmol) in THF (10 mL). Upon complete addition, the reaction was heated at reflux for 14 hours. After cooling, water (200 mL) was added and the mixture extracted with ethyl acetate (250 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo and the resulting residue purified by silica chromatography eluting with 1:1 ethyl acetate/cyclohexane to give the title product (2.43 g) LC retention time 3.10 mins MS m/z 286 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:16]12([N:26]=[C:27]=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)CC)C.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][C:27]([NH:26][C:16]34[CH2:25][CH:20]5[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]5)[CH2:23]3)[CH2:17]4)=[O:28])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: N[C@H]1CC[C@@H](Oc2ccc(F)cc2)CC1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@@H](Oc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution compound 10 in DMF was added 1-adamantyl isocyanate (0.16 g, 0.91 mmol) followed by triethylamine (0.10 g, 1.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was recrystallized from DCM/hexanes. Yield: 0.31 g (88% of theory). M.P.: 207° C. 1H NMR (300 MHz, CDCl3): δ 6.98-6.91 (m, 2H), 6.84-6.78 (m, 2H), 4.34 (s, 1H), 4.30 (d, J=9.8 Hz, 1H), 4.20 (s, 1H), 3.71-3.56 (m, 1H), 2.13-1.44 (m, 23H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=O)[CH3:21])[C:16]2[CH:23]=[CH:24][N:25]=[CH:26][C:15]1=2)(=O)[CH3:12]>CC(OC)(C)C>[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([CH2:11][CH3:12])[C:15]2[CH:26]=[N:25][CH:24]=[CH:23][C:16]1=2)[CH3:21]
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: COC(C)(C)C
Product: CCN1CCN(CC)c2cnccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.56 g (11.69 mmol) of AlCl3 were suspended in 60 ml of MTBE at room temperature. After stirring for 45 minutes, the reaction mixture was cooled to 0° C. and LiAlH4 (1.32 g, 34.65 mmol) was added a little at a time. After the addition was complete and the mixture had been stirred for another 15 minutes, compound 8 (1.00 g, 4.56 mmol) was added and the mixture was stirred at 0° C. for another hour. The reaction mixture was subsequently refluxed for 8 hours and after cooling to room temperature was poured into ice water. The precipitated inorganic solid was filtered off with suction and washed twice with 30 ml of DCM. The aqueous phase was brought to a pH of 12 and extracted three times with 40 ml of DCM. The combined extracts were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product was purified by flash chromatography on silica gel (EtOAc/MeOH/NEt3, 10:0.5:1). This gave 0.52 g (60%) of a colorless oil which solidified in the freezer. Rf=0.47 (EtOAc/MeOH/NEt3, 10:0.5:1). 1H NMR: (400 MHz, CDCl3): δ=1.15 (q, 3J=14 Hz, 6H, CH3), 3.22 (m, 3J=6 Hz, 2H, H-3), 3.23 (m, 2J=14 Hz, 4H, CH2), 3.42 (m, 3J=6 Hz, 2H, H-2), 6.34 (d, 3J=5.2 Hz, 1H, H-8), 7.69 (s, 1H, H-5), 7.75 (d, 3J=5.2 Hz, 1H, H-7). 13C NMR: (100 MHz, CDCl3): δ=10.1, 10.4 (CH3), 44.6, 46.5 (CH2, C-2, C-3), 44.9, 45.0 (CH2), 104.0 (C-8), 130.5, 130.1 (Cq), 131.8 (C-5), 140.7 (C-7). GC-MS (EI): RT 8.63 min, m/e (%): 192 (10), 191 (M+, 100), 190 (4), 177 (8), 176 (95), 175 (5), 162 (11), 161 (8), 160 (5), 148 (13), 147 (10), 146 (8), 135 (2), 134 (9), 133 (6), 131 (8), 121 (2), 119 (4), 118 (3), 107 (3), 104 (2), 92 (2), 91 (2), 80 (8), 77 (4) IR (KBr): ν=3436 (s), 3112 (w), 3019 (w), 2964 (w), 1661 (s), 1686 (vs), 1583 (m), 1497 (m), 1409 (s), 1363 (w), 1332 (m), 1311 (s), 1260 (m), 1249 (w), 1232 (m), 1220 (m), 1180 (m), 1150 (w), 1119 (m), 1064 (w), 1035 (m), 985 (m), 970 (m), 886 (s), 858 (m), 847 (m), 802 (m), 765 (w), 740 (w), 704 (w), 647 (w), 614 (w), 592 (w), 577 (m), 570 (m), 507 (w) cm−1. HRMS (EI) calculated for C11H17N3 [M+]: 191.1422; found: 191.1430.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl.[Cu]>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Yield: 63.1 %

Procedure:
32.0 g (191 mmol) of carbazole, 50.0 g (229 mmol) of 4-iodotoluene, 2.02 g (31.9 mmol) of copper powder, 16.8 g (53.7 mmol) of 18-crown-6-ether and 29.0 g (210 mmol) of potassium carbonate were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added 300 ml of o-dichlorobenzene as solvent. The resultant product was heated to 180° C. under a nitrogen flow in a silicone oil bath, and subjected to the reaction for 113 hours. After the reaction was completed, the reaction product was subjected to suction filtration with a suction funnel, before it was cooled down. The resultant filtrate was concentrated in an evaporator. To the resultant oily product was added 200 ml of methanol. The precipitated solid was subjected to the filtration at a reduced pressure with a suction funnel to obtain a gray solid, which was recrystallized in the presence of benzene to obtain 31.0 g of a white crystal.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:9]([F:8])([F:20])[F:19])[CH:17]=1
Reactant: C[C@@H]1CCC[C@H]1O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CCC[C@H]1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Trans-2-Methylcylopentanol (50 mg, 0.5 mmol) was added to a flame dried round bottom flask under nitrogen containing 0.5 mL of dry tetrahydrofuran (“THF”) and cooled to 0° C. A 1.0 M solution of potassium t-butoxide in t-butanol (0.5 mL) was added dropwise and the reaction mixture stirred at 0° C. for 0.5 h. The above solution was then transferred via syringe to a flask containing 2-Trifluoromethyl-4-fluoro-benzonitrile (95 mg, 0.5 mmol) in 0.5 mL of THF at 0° C. The mixture was stirred at 0° C. for 3 h, warmed to room temperature and stirred for 16 h. The reaction mixture was then cooled to 0° C., poured into a seperatory funnel containing 8 mL of water, and extracted with 10 mL of methyl tert-butyl ether. The organic phase was washed with water, brine, dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 112 mg 4-(trans-2-Methyl-cyclopentyloxy)-2-trifluoromethyl-benzonitrile. GC/MS: 269 (M/Z for C14H14F3NO).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5C=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:31]1C=CC=CC=1C1C=CC2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N=1>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:31]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12

Procedure:
7-Cyclobutyl-5-(2-pyridin-2-yl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described as described for 7-Cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline; 1H NMR (DMSO-d6, 400 MHz) δ 1.88-2.00 (m, 1H), 2.02-2.16 (m, 1H); 2.32-2.44 (m, 2H); 2.44-2.58 (m, 2H); 4.00-4.16 (m, 1H); 6.76 (brs, 2H); 7.45-7.59 (m, 1H); 7.94 (s, 1H); 7.94-8.05 (m, 2H); 8.13 (d, J=8.4 Hz, 1H); 8.24-8.32 (m, 1H); 8.51-8.68 (m, 3H); 8.72-8.80 (m, 1H); MS (ES+): m/z 394.08 (100) [MH+], HPLC: tR=3.14 min (MicromassZQ, polar—5 min).
Reaction SMILES: C([O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])([OH:20])[CH2:16][CH2:15]2)[CH:9]=[N:8][CH:7]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[OH:20][C:17]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:10]2[NH:11][C:6](=[O:5])[CH:7]=[N:8][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)[nH]1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
After dissolving 274 mg of 1-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was allowed to stand at room temperature for 2 hours. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (186 mg, 79% yield).