Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:75]1[CH:80]=[C:79]([F:81])[CH:78]=[C:77]([Cl:82])[CH:76]=1>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:82][C:77]1[CH:76]=[C:75]([NH:1][CH:2]([C:4]2[CH:5]=[C:6]([C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]3=[O:20])[CH3:3])[CH:80]=[C:79]([F:81])[CH:78]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(Nc1cc(F)cc(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 95 °C
Yield: 66.9 %

Procedure:
To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol, single enantiomer, [α]D20°: +35° in acetonitrile), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-3-chloro-5-fluorobenzene (467 mg, 2.23 mmol) in degassed 1,4-dioxane (2 ml), was added tris(dibenzylideneacetone)dipalladium (70 mg, 0.08 mmol). The suspension was heated in a sealed container at 95° C. for 16 hrs. The reaction mixture was filtered through a short pad of dicalite and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 8% isopropanol in DCM. The solvent was evaporated to dryness, the product triturated with diethyl ether—DCM (9:1), collected by filtration and dried to afford 8-(1-(3-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (320 mg; 67%) as a clear yellow solid. Mass Spectrum: M+H+ 474. [α]D20°: −138°. NMR Spectrum (DMSOd6): 1.52 (d, 3H), 2.75 (bs, 3H), 2.95 (bs, 3H), 3.49-3.63 (m, 4H), 3.70-3.79 (m, 4H), 4.98-5.07 (m, 1H), 5.60 (s, 1H), 6.23 (d, 1H), 6.42 (d, 1H), 6.43 (ddd, 1H), 6.94 (d, 1H), 7.54 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH3:39])=[CH:31][N:30]=1.C([O-])(=O)C.[K+].O>C(=O)(O)[O-].[Na+].O1CCOCC1>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH3:39])=[CH:31][N:30]=1
Reactant: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCOCC4)cnc3F)n2)cc1
Temperature: 120 °C
Yield: 52.5 %

Procedure:
A glass microwave reaction vessel was charged with 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.433 g, 1.126 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (0.260 g, 1.023 mmol), potassium acetate (0.308 g, 3.14 mmol), Am-Phos (0.051 g, 0.082 mmol), dioxane (3 mL) and water (0.5 mL, 27.8 mmol). The reaction mixture was stirred and heated in a CEM Explorer Microwave Unit for 10 min at 120° C., while 100 Watts of energy was supplied via Powermax® (simultaneous heating while cooling technology). The reaction mixture was diluted with sat. sodium bicarbonate (10 mL) and extracted with chloroform (3×10 mL). The organic extracts were combined and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (40 gram), eluting with 50% ethyl acetate/hexanes to give 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.300 g, 0.537 mmol, 52.5% yield) as a light-yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 8.46 (d, J=9.59 Hz, 1H) 8.31 (d, J=1.57 Hz, 1H) 7.25 (d, J=7.63 Hz, 4H) 6.90 (dd, J=10.27, 8.71 Hz, 4H) 4.77 (d, J=13.30 Hz, 3H) 3.66-3.79 (m, 6H) 3.47-3.61 (m, 5H) 3.36 (s, 4H) 3.18 (d, J=5.09 Hz, 1H) 2.49-2.53 (m, 3H) 2.40 (s, 2H) 2.14-2.34 (m, 2H). m/z (ESI, +ve ion) 559.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([O:20]CC)=[O:19])[CH3:2].[Li+].[OH-]>CCO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A mixture of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.196 mol) and LiOH (30 g, 0.6 mol) in EtOH (200 mL) and water (100 mL) was stirred at RT for 16 h. The mixture was concentrated. The residue was diluted with water (300 mL) and was washed with EtOAc (100 mL). The aqueous layer was acidified to pH<2 with conc HCl and was extracted with EtOAc (3×300 mL). The extracts were washed with brine, dried over Na2SO4 and concentrated. Petroleum ether (PE) (200 mL) was added. The resultant precipitate was collected by filtration, washed with PE and dried to afford 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid. (43 g, 78.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 6.58 (d, J=7.6 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(O[C:14]([S-])=[S:15])C.[K+].Cl>N1C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(O)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc2oc(=S)[nH]c2c1
Temperature: 0 °C
Yield: 46 %

Procedure:
A mixture of 3-amino-4-hydroxybenzonitrile (50 mg, 0.37 mmol) and potassium O-ethyl-xanthate (65 mg, 0.41 mmol) in pyridine (0.75 mL) was heated at reflux for 2 h. After cooling, the mixture was poured into ice-water. Then concentrated hydrochloric acid (0.2 mL) was added. The solid was collected, washed with water and dried to give 2-thioxo-2,3-dihydro-benzooxazole-5-carbonitrile 30 mg (46%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:46][CH2:45][C:43]3[CH:42]=[CH:41][N:40]=[C:39]([C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=4)[CH:44]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A solution of acid 18 (0.50 g, 1.62 mmol) in THF (25 mL) was added with DEPC (0.32 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10′. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.47 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water (40 mL) was added to the residue that was extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale yellow oil (0.31 g). Yield=35%, 1HNMR (DMSO, 200 MHz) δ 1.22 (t, 3H), 1.40 (bs, 2H), 1.61 (bs, 2H), 4.16 (q, 2H), 4.42 (d, 2H, J=6.1), 7.26 (m, 2H), 7.46 (d, 2H, J=8), 7.6 (dd, 1H), 7.87 (s, 1H), 8.21 (d, 2H, J=7.9), 8.25 (t, 1H), 8.60 (d, 1H, J=4); [M+1] 560.01 (C23H21ClF3N3O4S2 requires 559.06).
Reaction SMILES: O[N:2]=[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]>C(O)C.[Pd]>[NH2:2][CH:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCC(=NO)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(N)c1ccccc1
Yield: 107.6 %

Procedure:
1,1-Dimethylethyl 4-(hydroxyimino)-4-phenylbutylcarbamate (2.3 g, 8.3 mmol), in absolute ethanol was hydrogenated over 10% palladium on charcoal (0.5 g) at 5 bar pressure for 20 h. The mixture was then filtered and the filtrate concentrated to dryness to afford the title compound as a colourless oil (2.36 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C([Li])CCC.Cl[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[O:11][CH2:18][Si:19]([O:20][CH2:21][CH3:22])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCO[Si](COc1c(F)c(F)cc(F)c1F)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.32 g (20 mmol) of 2,3,5,6-tetrafluorophenol are dissolved in 50 ml of toluene, and 8 ml of n-butyllithium (2.5 M in hexane) are added at 0° C. After warming to room temperature, the solution is stirred for a further 2 hours. Then 4.3 g of (chloromethyl)triethoxysilane (20 mmol) are added dropwise and the reaction mixture is boiled under reflux for 6 hours. The resulting suspension is filtered and the solvent is stripped off in vacuo. The pale yellow liquid which remains is subjected to fractional distillation.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[Cl:17][C:18](Cl)([Cl:22])[C:19](Cl)=[O:20]>CCOCC>[Cl:17][C:18]1([Cl:22])[C:19](=[O:20])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(C#Cc2ccccc2)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C2(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of l-(methylthio)-4-(phenylethynyl)benzene (method 6, 20 g) and Zn(Cu) couple (17.3 g) in anhydrous ether (450 mL) at 15° C. was added trichloroacetyl chloride (32.4 g) dropwise (over 3h). Internal temperature was maintained between 13°-16° C. during addition. The mixture was stirred at r.t. for 18 hr, filtered through a pad of celite®, washed with a saturated NH4Cl sol., saturated NaCHO3 sol., brine, dried (MgSO4) and the solvents evaporated. The resulting residue was first purified by flash chromatography (silica gel; hexane/EtOAc (98:2 to 90:10)) and then the resulting solid was stirred vigorously in Et2O for 3 hr and filtered to afford the title compound as a pale yellow solid, m.p. 99°-100° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3](O)[CH3:4].[CH3:7][S:8]([OH:11])(=[O:10])=[O:9]>>[CH3:7][S:8]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][O:9][S:8]([CH3:7])(=[O:11])=[O:10])(=[O:10])=[O:9]
Reactant: CC(O)CCO
Reactant: CS(=O)(=O)O
Product: CS(=O)(=O)OCCCCOS(C)(=O)=O

Procedure:
Into a four-necked flask, fitted with a mechanical stirrer, condenser, thermometer and a Nitrogen inlet was added 665.53 g (1.40 moles) of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer, from Example 2, and 240.43 g (2.67 moles) of 1,3-Butanediol. With the reaction mixture at 30-35° C., 131.89 g (1.37 moles) of Methanesulfonic Acid (MSA) was slowly added to neutralize the amine. The reaction was monitored by measuring the Acid Value and Base Value of the reaction mixture over time. When Methanesulfonic salt of PPG-4-N-Methyl-N,N-Diethanolamine Adipate oligomer was formed, 120.51 g (1.30 moles) of Epichlorohydrin was charged. The reaction temperature was increased to 85-90° C. and kept under Nitrogen blanket while it stirred for the next 6 hours. Reaction was monitored by the drop in Acid Value. When the acid value stabilized, 541.63 g (1.6105 moles) of Cinnamidopropyldimethylamine was charged (Cinnamidopropyldimethylamine was prepared as disclosed in example 1 in U.S. Pat. No. 5,633,403). The reaction mixture was stirred for 6 hours at 85-90° C. and was monitored by a drop in Base Value. When the base value drop stabilized, the product was diluted with water to 64-68% actives to improve fluidity. The resulting product, [Poly(N-Hydroxypolyoxypropylethyl) N-Adipyl-Poly-Oxypropyl)-N-Methyl-N-(2,Hydroxy-3-Cinnamidopropyl Dimethyl Ammonium Chloride) Methane Sulfonate] was obtained as a viscous yellow liquid.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:6]2[C:7]3[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][C:8]=3[CH:21]=[CH:22][C:23]=2[S:24](Cl)(=[O:26])=[O:25])([O-:4])=[O:3]>CO>[N+:2]([C:5]1[C:6]2[C:7]3[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:9][C:8]=3[CH:21]=[CH:22][C:23]=2[S:24]([NH2:1])(=[O:26])=[O:25])([O-:4])=[O:3]
Reactant: N
Reactant: O=C(N1Cc2ccc([N+](=O)[O-])c3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Solvent: CO
Product: NS(=O)(=O)c1ccc2c3c(ccc([N+](=O)[O-])c13)CNC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2M solution of ammonia in methanol (10 mL) is added to a solution of 7-nitro-2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline-6-sulfonyl chloride (4 mmol) in 40 mL of methanol and the resulting mixture is stirred at room temperature for 24 hours. The mixture is then concentrated under vacuum and the residue is partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate and concentrated to afford the title compound. The crude product can be purified by recrystallization or chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:19][N:20]=[N+]=[N-])[CH2:15][N:16]=[N+]=[N-])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:15][NH2:16])[CH2:19][NH2:20])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CN=[N+]=[N-])CN=[N+]=[N-])cc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(C(CN)CN)cc1
Yield: 84.1 %

Procedure:
[4-(2-Azido-1-azidomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (240 mg, 0.757 mmol, as prepared above) was hydrogenated at 40 psi H2 over 10% Pd/C (120 mg) for 1 h. The reaction mixture was filtered through a pad of Celite, concentrated and dried in vacuo to afford [4-(2-amino-1-aminomethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (169 mg, 64%): 1H-NMR (CD3OD; 400 MHz): δ 7.35 (d, 2H, J=8.6 Hz), 7.12 (d, 2H, J=8.6 Hz), 2.90 (m, 2H), 2.79 (m, 2H), 2.69 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:3][CH:4]=1
Reactant: CCCCCCN
Reactant: Brc1ccc(Br)cc1
Product: CCCCCCNc1ccc(Br)cc1
Yield: 82.8 %

Procedure:
Using the general procedure, 1,4-dibromobenzene (236 mg, 1.0 mmol) was coupled with n-hexylamine (158 μL, 1.2 mmol) at 90° C. for 20 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (212 mg, 83% yield). Rf=0.6 (hexane/ethyl acetate=10:1).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)n(C(C)(C)C)n1

Procedure:
158 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2,3-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:20].[CH2:21]([O:23][C:24](=[O:34])[CH2:25]C1C=CC(NN)=CC=1)[CH3:22]>>[ClH:20].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[C:7]([NH2:19])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9]2)=[CH:11][CH:12]=1)[CH3:22].[ClH:20]
Reactant: CCOC(=O)Cc1ccc(NN)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
The title compound was prepared in the same manner as described for 5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine, replacing 4-nitrophenylhydrazine with ethyl(4-hydrazinophenyl)acetate hydrochloride (11.98 g, 51.9 mmol). The title compound was obtained as a white solid (HCl salt, 11.95 g) in 68% yield. 1H-NMR (DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 5.59 (s, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.77 (s, 2H), 1.27 (s, 9H), 1.20 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]+=302.3, RT=2.44 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:6]=[CH:7][CH:8]=1>Br>[CH3:14][C:12]1[N:13]=[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[O:10][CH:11]=1
Reactant: COc1cccc(-c2nc(C)co2)c1
Agent: Br
Product: Cc1coc(-c2cccc(O)c2)n1
Yield: 95.6 %

Procedure:
A solution of 2-(3-methoxyphenyl)-4-methyloxazole (1.1 g, 5.79 mmol) in aqueous hydrogen bromide (10 mL, 48% w/w) was heated to 100° C. for 16 h. The mixture was concentrated to give 3-(4-methyloxazol-2-yl)phenol (0.97 g, crude), which was used without purification. LCMS MH+ 176.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[OH:26])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.[I-].[K+]>C1COCC1.CN(C=O)C>[C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([C:28]3[O:27][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)=[CH:37][CH:38]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of trans-2-triphenylmethylaminocyclopentanol (4.76 g; 13.85 mmol), is added Nail (60%; 0.83 g; 20.78 mmol) in 100 ml THF and 20 ml DMF. This mixture is stirred for 1 hr. and then 4-(benzoxazol-2-yl)benzyl bromide (3.99 g; 13.85 mmol) is added followed by potassium iodide (pinch). The reaction mixture is stirred for 72 hrs., quenched with water, concentrated in vacuo and flash chromatographed using 9:1; hexane:EtOAc to obtain trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane which is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20]Cl)[CH:19]=1.[H-].[Na+]>>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][N:7]2[CH2:8][CH2:9][CH2:10][C@H:6]2[CH2:5][O:4][CH2:3][C:2]([F:1])([F:11])[F:12])[CH:19]=1
Reactant: FC(F)(F)COC[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)COC[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-2-(2,2,2-trifluoro-ethoxymethyl)-pyrrolidine was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow oil. MS: 353.1, 355.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH3-]C#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:3][N:2]([C:4](=[O:13])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH3:1])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(N)C(=O)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCO
Product: CN(NC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of (4-fluorophenyl)-acetic acid N-methyl-hydrazide, 8, (2 g, 11 mmol) in ethanol (20 mL) is added commercially available 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.19 g, 11 mmol). The reaction mixture is refluxed for 30 minutes, then cooled to room temperature after which NaCNBH3 (1.04 g, 16,5 mmol) is added. The pH of the reaction mixture is adjusted to about 3 with concentrated HCl and the reaction mixture stirred for 3 hours at room temperature. The mixture is neutralized with saturated sodium bicarbonate and extracted three times with CH2Cl2. The combined organic layers are dried, filtered and concentrated in vacuo. Purification over silica (EtOAc) affords 3.7 g (93% yield) of the desired product. ESI/MS: 366.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1OC)[NH2:38]>>[CH2:2]1[C:35]2[C:41](=[CH:40][CH:39]=[C:37]([NH:38][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc(N)cc1Cl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-chloro-4-(methyloxy)aniline in a manner analogous to Example 27, Step D. HRMS: calc. C31H22N6O2F2Cl (M+H)+ 583.1461 found 583.1453.