Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:33]1[C:34]2[C:30](=[C:29]([CH2:28][NH:27][C:26]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]([F:25])([F:23])[F:24])[CH:20]=3)=[O:38])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (130 mg, 0.22 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.24 mmol) in water (6 mL). The mixture was then stirred at room temperature overnight. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 0.1159 g (93%). MS m/e 565.9 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown; MS: [M+H]+=448.
Reaction SMILES: [N:1]#[C:2]Cl.[CH2:4]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:5]1([CH2:4][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:2]#[N:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: N#CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nccn1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 50 ml 4-neck flask with stirring bar, nitrogen bubbler, gas inlet tube, thermometer, septum and acetonitrile (20 ml) was bubbled cyanogen chloride (3.1 g, 50 mmol) (ice bath was used to avoid mild heat of solution). The reaction was cooled in an ice bath and a solution of 1-benzylimidazole (3.16 g, 20 mmol) in acetonitrile (ca. 5 ml) was added via syringe. The colorless solution turned yellow-orange and within a few minutes a yellow-orange crystalline solid started to form. After 1 hour, the thick slurry was cooled to -20° C. and triethylamine (7 ml, 50 mmol) was added at such a rate to prevent the temperature from rising above 0° C. The mixture was stirred 1 hour while warming to room temperature, poured into saturated aq NaHCO3 (100 ml) and extracted with ether (3×75 ml). The combined organic layers were dried (MgSO4), evaporated and purified by Kugelrohr distillation. After a forerun of diethylcyanamide, the desired product was collected at 130° C. (0.4 mm) (3.05 g, 83%) as a colorless liquid which crystallized on standing, mp 51°-52° C. (cyclohexane).
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[N:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.77 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.75 g), sodium carbonate (0.3 g) and sodium iodide (0.5 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.7 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (667 mg, 54%).
Reaction SMILES: [CH:1]1([NH2+]C2CCCCC2)CCCC[CH2:2]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O-:28])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][C:31]#[N:32])[C:26]([O:28][CH2:1][CH3:2])=[O:27])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: N#CCC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are added and the mixture is stirred for 10 minutes at ambient temperature. Then 50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed with semisaturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2cc(C(F)(F)F)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3cc(C(F)(F)F)ccc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 12 (240 mg, 0.57 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (96 μL, 0.68 mmol), methanesulfonyl chloride (53 μL, 0.68 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (3×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 17 was obtained (260 mg, 91% yield) as a crude yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[O:36]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37]1>>[O:36]1[CH2:40][CH2:39][CH:38]([C:41]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:42])[CH2:37]1
Reactant: O=C(O)C1CCOC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)C6CCOC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and tetrahydrofuran-3-carboxylic acid (Aldrich, Cat. No. 339954). LCMS (M+H)+: m/z=583.2.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].[CH2:13](Br)[C:14]#[CH:15].Cl>CS(C)=O>[CH2:15]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[C:14]#[CH:13]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: C#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCOc1cc(C=O)ccc1O
Temperature: 0 °C
Yield: 69.3 %

Procedure:
In a dry two-neck flask with a nitrogen inlet, NaH (4.8 g, 200 mmol, 2 equiv) was added into anhydrous DMSO (50 mL) in small portions. While stirring and cooling this solution to 0° C., anhydrous DMSO (60 mL) containing 3,4-dihydroxybenzaldehyde (13.8 g, 100 mmol, 1 equiv) was added dropwise into the flask. This reaction mixture was stirred at rt for 30 min. Propargyl bromide (11.1 mL 100 mmol, 1 equiv) was then added dropwise via syringe and the mixture was stirred at rt overnight. The mixture was poured onto ice, neutralized by a 1 M HCl solution and the product was extracted with ethyl acetate (3×250 mL). The combined organic extracts were concentrated to about 250 mL, washed with brine (5×250 mL) and dried over MgSO4. After filtration the solvent was removed under vacuum to afford crude product as a brownish powder. This was chromatographed on a silica gel column with an eluent of ethyl acetate/hexane/acetic acid (20/80/1) to give 8 as a white powder (12.2 g, yield: 69%). 1H NMR δ=9.84 (s, 1H, —CHO), 7.53 (d, J=1.7, 1H), 7.49 (dd, J1=1.7, J2=8, 1H), 7.09 (d, J=8, 1H), 6.22 (s, 1H, —OH), 4.84 (d, J=2.5, 2H, —OCH2), 2.60 (t, J=2.5, 1H, —C≡CH). 13C NMR δ=190.92 (—CHO), 152.20, 145.37, 129.96, 128.14, 115.35, 111.36, 77.41 (—C≡CH), 77.10 (—C≡CH), 57.23 (—OCH2). HRMS calculated for C10H8O3 (M+), 176.0473; found, 176.0465.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([Cl:28])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+]([C:4]([CH:7]1[CH:11]([O:12]C)[O:10][C:9](=[O:14])[CH2:8]1)([CH3:6])[CH3:5])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:11]([C:7](=[C:4]([CH3:6])[CH3:5])[CH2:8][C:9]([OH:14])=[O:10])=[O:12]
Reactant: COC1OC(=O)CC1C(C)(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 120 h
Yield: 74.6 %

Procedure:
A solution of 18.2 g of the product of Step A in 25 ml of methanol were added all at once to a solution of 18.9 g of sodium carbonate in 180 ml of water cooled to 0° C. and the mixture stood at room temperature for 120 hours. The mixture was washed with ether and cooled to 0° C. after which concentrated sulfuric acid was added to the mixture under an inert atmosphere until the pH was ≃1. The mixture was extracted with chloroform and then with ethyl acetate and the combined organic phases were dried and evaporated to dryness under reduced pressure to obtain 9.5 g of residue. The latter was crystallized from water to obtain 7.4 g of pure 3-formyl-4-methyl-pent-3-one-1-oic acid melting at 102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:15][CH3:16].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.C(=O)([O-])[O-]>COCCO>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(=O)N2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3C)ncc1Cl
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a solution of 7-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50 mg, 0.227 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (56 mg, 0.189 mmol) in 2.27 mL of 2-methoxyethanol was added 57 μL of 4M HCl in Dioxane (0.227 mmol). The solution was heated to 110° C. for 5 hrs, followed by the addition of MP-Carbonate (135 mg, 0.43 mmol) at RT. The MP-Carbonate was filtered after 30 minutes and the resulting crude material was chromatographed (ISCO) to give 2-[5-Chloro-2-(6-methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23 mg, 25%). 1H-NMR (CDCl3) δ 11.12 (s, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.51 (t, J=7.7 Hz, 2H), 7.43 (s, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.90 (t, J=8.8 Hz, 1H), 6.26 (br s, 1H), 3.80 (s, 3H), 3.33 (s, 3H), 3.04 (s, 3H), 2.0-2.4 (m, 6H); LC/MS (ESI-pos) m/z 481.06 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[NH4+]>O1CCOCC1.[Zn]>[NH2:32][C:28]1[CH:27]=[C:26]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)=[CH:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
400 mg (0.87 mmol) of N-tert-butyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-amine were dissolved in 15 ml of dioxane and 4 ml of water and 227 mg (3.48 mmol) of metallic zinc and 461 (8.7 mmol) of ammonium chloride were added. The mixture was stirred at 100° C. for 4 hours, then filtered through a celite pad. The filtrate was evaporated and the residue partitioned between dichloromethane and aqueous sodium hydrogenocarbonate. The organic phase was then dried and evaporated and the residue purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 from 9/1 to 7/3), giving 180 mg (48%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([Br:12])=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].[I-:14].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][I:14])=[N:7][CH:8]=[C:9]([Br:13])[N:10]=1
Reactant: O=C(CCl)Nc1ncc(Br)nc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CI)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 2-chloro-N-(3,5-dibromopyrazin-2-yl)acetamide (3.0 g, 9.11 mmol) in acetone (40 mL) was added sodium iodide (13.65 g, 91 mmol) dissolved in acetone (20 mL). Solution was allowed to stir at ambient temperature for 16 h. Solution was condensed under reduced pressure and diluted with ethyl acetate (500 mL) and washed consecutively with water (5×) to remove the blue color. Organics were dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the crude product. The solid was diluted with 10% ethyl acetate in hexanes (40 mL) and sonicated while scraping the sides of the flask. The solution was then heated under a heat gun for 5 min, then cooled while sonicating at ambient temperature. The resulting solid was filtered and washed with additional hexanes and dried under vacuum to afford the title compound (3.0 g, 7.13 mmol, 78% yield). MS (ESI) m/z 420.3 [M−1]+, 422.0 [M+1]+, 424.0 [M+3]+.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:9](O)(=O)[CH3:10]>>[CH3:9][C:10]1[O:4][CH2:3][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[N:1]=1
Reactant: CCC(N)(CO)CO
Reactant: CC(=O)O
Product: CCC1(CO)COC(C)=N1

Procedure:
The procedure described in Example 1 is repeated in all essential details with the exception that 2-amino-2-ethyl-1,3-propanediol and acetic acid are the initial reactants in a 1:1 molar ratio. These compounds are combined using the method of Purcell, U.S. Pat. No. 3,336,145 to form 2-methyl-4-ethyl-4-hydroxymethyl-2-oxazoline.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1ccccc1

Procedure:
1.62 g (1.40 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 46 g (268 mmol) of 1-naphthylboronic acid, 71 g (255.3 mmol) of 4-bromo-2-nitrobiphenyl and 93 g (433.9 mmol) of potassium carbonate in a mixture of 700 ml of water and 700 ml of THF, and the mixture is heated under reflux for 17 h. After cooling, the organic phase is separated off, washed three times with 400 ml of water and once with 400 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 83.1 g, 97.9% of theory; purity: 99.0% according to HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:24](=[O:26])[CH3:25])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (1.2 g) and acetic anhydride (0.36 ml) in dichloromethane (12 ml) was stirred at ambient temperature for 2 hours, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}acetamide (0.77 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](O)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.NC1C=CC=[C:20]2C=1C=[CH:23][C:22]([OH:26])=[CH:21]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]=2[CH:20]=[CH:21][C:22]([OH:26])=[CH:23]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Reactant: Nc1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3cc(O)ccc23)CC1
Yield: 37 %

Procedure:
Compound 53A is prepared according to the same procedure as that for 13A, using the following reactants: 8-aminonaphthalen-3-ol (10 g, 62.8 mmol), 2-chloro-N-(2-chlorethyl)-N-methylethananine hydrochloride (11.8 g, 62.8 mmol), sodium carbonate (3.32 g, 31.4 mmol), 1-butanol (200 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:29][C:24]1[C:23]([CH3:22])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:13]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccnc1C=O
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1cnccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1cnccn1
Yield: 63 %

Procedure:
Using General Procedure B: Reaction of [4-(1-pyrazin-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester and 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyrazin-2-yl-ethyl)-amino]-butyl}-carbamic acid tert-butyl ester (229 m, 63%) as an oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 6H), 1.43 (s, 9H), 1.50 (d, 1H, J=7.0 Hz), 2.30 (s, 3H), 2.90-2.96 (m, 2H), 4.05 (s, 2H), 4.08 (d, 1H, J=7.0 Hz) 7.10 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 8.37 (dd, 1H, J=5.1, 1.2 Hz), 8.39 (s, 1H), 8.48-8.50 (m, 1H), 8.63 (d, 1H, J=1.5 Hz).