Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:32][CH2:31]1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:43][C:42]4[CH:44]=[CH:45][C:39]([O:38][CH2:37][CH2:36][N:33]5[CH2:32][CH2:31][O:30][CH2:35][CH2:34]5)=[CH:40][CH:41]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(OCCN5CCOCC5)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (100 mg, 0.216 mmol) and 4-(2-morpholinoethoxy)aniline (58 mg, 0.26 mmol, 1.2 eq) using the method described in Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (20 mg, 15%). 1H-NMR (500 MHz, CDCl3) 1.45 (s, 9H), 1.67 (s, 9H), 2.58 (m, 4H), 2.8 (t, J=5.8 Hz, 2H), 3.73 (m, 4H), 4.11 (t, J=5.8 Hz, 2H), 6.54 (s, 1H), 6.6 (s, 1H), 6.91 (d, J=8.9 Hz, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.37 (s, 1H), 7.8 (s, 1H), 8.19 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH2:12][N:13]3C(OC(C)(C)C)=O)[CH2:10]2)=[N:6][CH:7]=1.Cl>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH2:12][NH:13]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(Br)cn3)[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 3.25 h
Yield: 1177.2 %

Procedure:
To the title compound of step A (149 mg, 0.0404 mmol) in EtOAc (1.5 mL) was added 4M HCl in dioxane (5 mL). After 3.25 h, the reaction was concentrated to give the title compound of step B (128 mg) which was used without further purification. MS (ESI) mass calcd. for C11H13BrN2O, 268.0. m/z found 269.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K].O>CN(C)C=O>[O:10]=[C:8]1[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:15])[N:9]1[CH2:2][C:3]#[N:4]
Reactant: N#CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of bromoacetonitrile (22 g) in N,N-dimethylformamide (200 mL) was added potassium phthalimide (34 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 27 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1)=[CH:7]2
Reactant: Nc1cccc2cc(O)ccc12
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Temperature: 90 °C

Procedure:
To a solution of 5-amino-2-napthol (2.8 g, 17.6 mmol) in DMF (20 mL), NaH (60% in oil, 843 mg, 21.1 mmol) was added and stirred until the bubbling stopped. To the mixture 4-chloro-N-methylpicolinamide (Org. Proc. Res. & Dev., 2002, 6, 777-781)(1 g, 5.86 mmol) was added and the reaction heated to 90° C. for 22 h. The mixture was cooled to RT and diluted with CHCl3 and washed with water. The emulsion was filtered thru a pad of Celite and the layers separated. The water was washed with CHCl3 and the organic portions combined and washed with 1N NaOH and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography using hexanes and EtOAc as the eluent to give the title compound as a rose-colored solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[IH:10]>CCCCCC>[I:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: I
Reactant: CSc1nccc(Cl)n1
Solvent: CCCCCC
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
4-Chloro-2-methylthiopyrimidine (40 g, 249 mmol) is added to Hydroiodic acid (57% in water, 200 mL). The suspension is vigorously stirred in the absence of light for 72 h at rt. A bright yellow solid formed which is collected by filtration. The solid is added to saturated aqueous NaHCO3 (500 mL) and stirred for 2 min. CHCl3 (600 mL) is added and the solid dissolved. The aqueous layer is extracted 2 times with CHCl3 (350, then 300 mL) and the organic extracts combined, washed with water (100 mL), dried over MgSO4 and filtered. The organic solvent is removed in vacuo to give colorless oil. Addition of n-hexane and removal of solvent again produced the title compound as a white solid (57.9 g, 230 mmol, 92%).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24]>CCO>[CH2:11]([O:10][C:2]([CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCSCCOCCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCCSCC)C(=O)OCC
Yield: 60 %

Procedure:
Sodium metal (0.31 g, 0. 014 mol) was dissolved in absolute EtOH (20 mL). To this mixture was added diethyl malonate (2.2 g, 0. 014 mol) in EtOH (5 mL) and the above 7-oxa-10-thiadodecyl bromide (3g, 0.011 mol) in EtOH (5 mL) at room temperature. The reaction mixture was refluxed for 5 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate (120 mL). The organic phase was washed with water (2×30 mL), brine (30 mL), and dried (Na2SO4). The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl- 9-oxa-12-thiatetradecanoate (2.3 g, 58%); bp 122°-128° C./0.04 torr; NMR: 1.27 (6H, t, J=7 Hz), 3.3-3.7 (5H, m), and 4.17 ppm (4H, q, J=7 Hz), 1.2-1.9 (10H, m ), 2.59 (2H, q, J=7 Hz), 2.68 (2H, t, J=7 Hz), 3.1-3.7 (5H, m), and 4.17 ppm (4H, q, J=7 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NC1N=C(N)C(CC2C=C[C:32]([OH:35])=C(OC)C=2)=CN=1>>[CH3:18][O:17][C:16]1[CH:15]=[C:14]([CH:11]=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:32]=[O:35]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: COc1cc(Cc2cnc(N)nc2N)ccc1O
Agent: Cl
Product: COc1cc(C=O)ccc1OCc1ccccc1

Procedure:
In a manner substantially analogous to that described in Example 1, Steps A-C, but substituting for 3-benzyloxy-4-methoxybenzaldehyde used therein, an equimolar amount of 3-methoxy-4-benzyloxybenzaldehyde, there is prepared 2,4-diamino-5-(3'-methoxy-4'-hydroxybenzyl)pyrimidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.[C:31]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C=O)c2)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1cccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A mixture of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde (0.80 g), diethyl malonate (0.37 g), benzoic acid (0.07 g), piperidine (0.05 g) and toluene (40 mL) was heated under reflux for 4 hrs. with azeotropic dehydration. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with acetone-hexane (1:5, v/v). To a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL) was added sodium borohydride (0.02 g) at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonate as an oil (0.71 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Br:16][CH2:17][CH2:18]Br>CN(C=O)C.O>[Br:16][CH2:17][CH2:18][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCBr)cc1
Temperature: 57.5 °C
Reaction time: 8 h

Procedure:
Anhydrous potassium carbonate (233 g, 1.68 mol) was added to a solution of 4-hydroxybezonitrile (100 g, 0.84 mol) in DMF (700 mL), and the resultant mixture was stirred for 1 h under a N2 atmosphere. 1,2-Dibromo-ethane (362 mL, 4.2 mol) was added slowly to the reaction mixture, which was then stirred at 55-60° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (3×750 mL). The combined organic layer was washed with water and then concentrated. The crude product was purified by column chromatography (silica gel: 60-120 mesh, eluent: petroleum ether-ethyl acetate, 90:10). Yield: 60 g (32%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: c1cocn1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27]>>[CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:24][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][OH:27])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC(CO)c1ccccc1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(CO)c2ccccc2)cc1
Yield: 83 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using N-dodecyl-4-formylbenzamide and 2-amino-2-phenylethanol gave the title compound as a white powder (83%). 1H NMR (CD3OD, 300 MHz) δ 7.79 (d, J=8.3 Hz, 2H), 7.44-7.26 (m, 7H), 3.85-3.56 (m, 5H), 3.39 (t, J=7.2 Hz, 2H), 1.71-1.58 (m, 2H), 1.47-1.25 (m, 18H), 0.92 (t, J=6.8 Hz, 3H) M−(LC/MS(ESI)): 437.5; M+(LC/MS(ESI)): 439.6 HPLC (Condition A), Rt: 4.26 min (HPLC purity: 98.8%).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH3+:6].[CH3:10][N:11]([CH3:14])[C:12]#[N:13]>O>[I:2][C:3]1[CH:4]=[C:5]([NH:6][C:12](=[NH:13])[N:11]([CH3:14])[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: [NH3+]c1cccc(I)c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: O
Product: CN(C)C(=N)Nc1cccc(I)c1
Temperature: 130 °C
Yield: 81 %

Procedure:
46.00 g (0.21 mol) of 3-iodoaniline were admixed with 100 ml of 15% strength hydrochloric acid. The 3-iodoanilinium hydrochloride formed was filtered off with suction, recrystallized from water and dried under reduced pressure (yield: 52.57 g=98%). The total amount of the anilinium salt was mixed with 14.42 g (0.205 mol) of dimethylcyanamide and heated at 130° C. for 10 minutes on an oil bath. After the reaction had abated, the reaction mixture was cooled, admixed with 100 ml of water and the water-soluble constituents were filtered off. The aqueous solution was extracted twice with 100 ml each time of diethyl ether, adjusted to a pH of 10-12 using KOH and subsequently extracted three times with 100 ml of dichloromethane. The CH2Cl2 extracts were dried over magnesium sulfate and the solvent was then taken off under reduced pressure. This left 48.2 g of N′-(3-iodophenyl)-N,N-dimethylguanidine as a colorless solid (yield: 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:12][C:13]([N:15]3[CH:21]4[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])([CH3:10])[CH3:11])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(-c2ccc(F)cc2)c1
Yield: 61.4 %

Procedure:
Using general procedure E, N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), 4-fluorophenyl boronic acid (91 mg, 0.65 mmol) and palladium (II) acetate gave the title compound as an off-white solid (64 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 2H), 7.37-7.30 (m, 2H), 7.10-7.03 (m, 3H), 4.77 (s, 1H), 3.99 (br s, 1H), 3.58 (m, 2H), 3.10-2.90 (m, 6H), 1.98 (m, 2H) 1.71 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 163.7, 161.3, 159.5, 157.1, 155.6, 144.6, 131.0, 130.9, 127.4, 127.2, 125.7, 116.1, 115.6, 57.9, 55.2, 48.2, 46.4, 46.4, 41.5, 30.6, 30.6, 27.6, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.90 min; (M+1) 400.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[C:26]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[C:26]3[CH2:32][NH:31][CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C(=O)OC(C)(C)C)CC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.05 mmol) in dichloromethane (2 mL) was added to tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(3-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (14 mg, 0.03 mmol) and stirred at rt for 1 hour. The solvents were removed under reduced pressure and the product was used without further purification. MS (ES+) m/z 457.3 (M+H)+
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)/[C:9]1=[O:34])=C)(C)(C)C.[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:51])=[C:40]([CH:42]=[N:43][C:44]([O:46][Si](C)(C)C)=[CH2:45])[CH:41]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH2:45][C:44](=[O:46])[NH:43][CH:42]3[C:40]3[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=3[CH3:51])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: C=C(OC(C)(C)C)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC2CCOCC2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2CCOCC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 33.2 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-1-(1-tert-butoxy-vinyl)-6-chloro-3-[5-chloro-2-(tetrahydro-pyran-4-ylmethoxy)-benzylidene]-1,3-dihydro-indol-2-one (2 g, 3.97 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 mmol) in toluene to give the title compound as a white solid (770 mg).
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:17](#[N:20])[CH:18]=[CH2:19]>C(O)C>[OH:16][CH2:15][C:2]1([NH:1][CH2:19][CH2:18][C:17]#[N:20])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNC1(CO)CCN(Cc2ccccc2)CC1

Procedure:
A. mixture of 4-amino-1-(phenylmethyl)-4-piperidinemethanol (0.0182 mol) and 2-propenenitrile (0.0304 mol) in ethanol (80 ml) was stirred and refluxed over the weekend. 2-Propenenitrile (2 ml) was added. The mixture was stirred and refluxed for 5 hours. 2-Propenenitrile (2 ml) was added again. The mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 3-[[4-(hydroxymethyl)-1(phenylmethyl)-4-piperidinyl]amino]-propanenitrile (interm. 10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](Br)[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]([C:18](=[S:22])[O:19]CC)[NH2:17]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[S:22][C:18](=[O:19])[NH:16][N:17]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=S)NN
Reactant: CC(Br)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: CC1SC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 23 %

Procedure:
22 g (75 mM) of 1-(4-chloro-3-nitrophenyl)-2-bromopropan-1-one and 8 ml (75 mM) of O-ethyl hydrazinecarbothioate in 150 ml of ethanol are refluxed for 16 hours with stirring. The reaction medium is then concentrated under vacuum and the residue obtained is taken up in water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then dried over anhydrous sodium sulfate. The solvent is evaporated off under vacuum to give an oil, which is purified on a column of silica using a dichloromethane/acetone mixture (95/5) as eluent. 5 g of 5-(4-chloro-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cccc(CNC2CC2)c1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: Cc1cccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:5]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1COCC1.Cl>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:3][C:4]2[N:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:5]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
To a suspension of NaH (152 mg, 3.8 mmol, 60% dispersion in mineral oil) in anhydrous THF (2 mL) at room temperature was slowly added a solution of 2-amino-4-(trifluoromethyl)-6-(2,2,2-trifluoroethoxy)pyrimidine (0.50 g, 1.9 mmol) in anhydrous THF (2 mL) and the resulting mixture was stirred 20 min. To the mixture was added 4-trifluoromethylphenyl isocyanate (326 μL, 2.28 mmol) and the resulting mixture was allowed to stir at room temperature. After 18 h of stirring the reaction mixture was diluted with 2 N HCl (30 mL). The acidic mixture was extracted with ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated. The resulting residue was mixed with ethyl acetate (30 mL), diluted with hexane (100 mL) and allowed to stand at room temperature. After 18 h the insoluble material was filtered and dried in a vacuum oven (50° C.) to afford 102 as a white solid (379 mg, 44% yield): m.p. 197-199° C.; 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 10.71 (s, 1H), 7.72 (app s, 4H). 7.35 (s, 1H), 5.25-5.16 (q, 2H, J=8.9 Hz); ESI/MS 448 (M+H), 447 (M−H).