Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:30]/[OH:31])/[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(S(C)(=O)=O)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(S(C)(=O)=O)c2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-(2-methylpyridin-4-yl)-3-(3-(methylsulfonyl)-phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
207 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 86 mg of 2-aminopyrazine, 79 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 111 mg of sodium t-butoxide and 43 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 4 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 202 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 128 mg of the objective compound as pale orange powder.
Reaction SMILES: C([S:5][CH2:6][C@:7]([CH3:12])([C:9]([OH:11])=[O:10])[NH2:8])(C)(C)C.[ClH:13]>>[ClH:13].[CH3:12][C@:7]([C:9]([OH:11])=[O:10])([CH2:6][SH:5])[NH2:8]
Reactant: CC(C)(C)SC[C@@](C)(N)C(=O)O
Agent: Cl
Product: C[C@@](N)(CS)C(=O)O
Temperature: 25 °C
Yield: 85.3 %

Procedure:
S-tert-butyl-α-methyl-D-cysteine (20 g) was dissolved in conc. hydrochloric acid (180 g), and the resultant solution was refluxed under heating for 45 hours. The reaction solution was allowed to cool down to room temperature, and then concentrated to 35 g. Then, the solution was heated to 40° C., and toluene (110 mL) was added to the solution, followed by concentration to about 40 g. This operation was further repeated four times, and the produced solid was filtered off and dried under vacuum at 60° C. for 48 hours to obtain the title compound as a white solid (15.3 g). As a result of HPLC analysis (column: CAPCELL PAK SCX (produced by Shiseido Co., Ltd.), mobile phase: potassium dihydrogen phosphate-phosphoric acid solution (pH 2.0)/acetonitrile=95/5, flow rate: 0.3 ml/min, detection wavelength: 210 nm, column temperature: 30° C.), it was confirmed that the solid was the desired compound (yield 84.6%). The measurement of optical rotation showed [α]D20=−6.28 (c1. 21, H2O). Since the sign of the optical rotation was opposite to that of the α-methyl-L-cysteine hydrochloride produced in EXAMPLE 10, it was confirmed that the obtained compound was the intended D-stereoisomer.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=1[N+:27]([O-:29])=[O:28])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (54.6 g, 60%, 1.365 mol) in 600 mL of DMF was added di-t-Butyl malonate (118 g, 0.546 mol) at 0° C. and stirred for 30 min. 2,4,6 trifluoronitrobenzene was added as a solution in 400 mL of DMF (75 g, 0.42 mol) over 3 hours and the solution stirred at ambient temperature for 12 hours. The reaction mixture was extracted with ethyl acetate (3X's). The ethyl acetate was washed with water (3X's) and with brine and dried over MgSO4 and concentrated to give 62 g of crude product. LCMS [M+Na]-396; 1H NMR (500 MHz, DMSO) δ 7.81 (m, 1H), 7.27 (m, 1H), 5.00 (s, 1H), 1.41 (m, 18H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH:10]1([CH2:9][NH:8][C:6]([C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:25]=4)[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)=[O:7])[CH2:12][CH2:11]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
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: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 59.3 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25 mg, 0.098 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 18) (30 mg, 0.074 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 80° C. in DMF (1 ml) for 18 hours. The reaction was absorbed onto silica, applied to a bond-elut (10 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%), then acetone and methanol. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-(3-[5-(cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamide as a white solid (20 mg). LCMS: retention time 2.42 min, MH− 456. NMR: δH [2H6]-DMSO 10.32, (1H, s), 9.09, (1H, s), 8.82, (1H, t), 8.28, (1H, m), 8.19, (1H, m), 7.85, (1H, t), 7.76, (1H, m), 7.64, (1H, m), 7.31, (1H, m), 6.98, (1H, m), 6.88, (1H, s), 3.43, (4H, m), 3.18, (2H, m), 2.31, (3H, s), 1.95, (4H, m), 1.07, (1H, m), 0.45, (2H, m), 0.25, (2H, m).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]1[C@H:13]2[O:14][C@H:10]([C@H:11]([C:18]([OH:20])=[O:19])[C@@H:12]2[C:15]([OH:17])=O)[CH2:9]1>C1C=CC=CC=1>[CH2:9]1[CH:10]2[O:14][CH:13]([CH:12]3[C:15](=[O:17])[O:20][C:18](=[O:19])[CH:11]32)[CH2:8]1
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)[C@H]2CC[C@@H]1O2
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2C3CCC(O3)C12
Temperature: 80 °C
Yield: 50.6 %

Procedure:
As shown in scheme 1, we prepared endothal anhydride by adding acetic anhydride (0.5 mL) (4) to a suspension of Endothall (186 mg) (3) in benzene (3 mL) and the mixture was then stirred until the solid had gone into solution (2 hours). The solution was heated under vacuum to remove the benzene and the residue was then heated at 80° C. for 30 min. Petroleum ether (5 mL) was then added and the desired anhydride spontaneously crystallized. The product was removed by filtration washed with a little petroleum ether to give the pure product (85 mg) which was used immediately in the following two preparations.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH:6]=1.O([Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])S(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[Si:20]([O:10][C:8]([CH3:11])([CH3:9])[CH2:7][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(O)Cn1cnc(I)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CC(C)(Cn1cnc(I)c1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol was dissolved in DCm and lutidine was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 min then tert-butyldimethylsilyl triflate (TBSOTf) was added dropwise. The mixture was waremed to room temperature and sitted for about an hour, then quenched with 30% acetic acid, extracted ethylacetate, dried, and concentrated to give 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole (Yield=74%). LC-MS: m/z=381 [M+H+]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(S(C)(=O)=O)cc3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Yield: 26.8 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (257 mg, 0.37 mmol), 4-methanesulfonylphenylboronic acid (153.8 mg, 0.75 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40.9 mg, 0.056 mmol), and cesium carbonate (245.5 mg, 0.75 mmol) to afford 4-[3-[6-(5,4′-bis-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (71 mg, 26.4%) as a light brown viscous oil: ES(+)-HRMS m/e calcd for C37H48O10S2 (M+H)+ 717.2762, found 717.2758.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:6](=[C:13](/[NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:23][CH:22]=2)\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:5]1=[O:38])(=O)C.[CH3:39][N:40]([CH3:45])[C:41](=[O:44])[CH2:42]Br.CC(C)([O-])C.[K+].[OH-].[Na+]>CS(C)=O.CO>[CH3:39][N:40]([CH3:45])[C:41]([CH2:42][N:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20]/[C:13](=[C:6]2\[C:5](=[O:38])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:25]=1)[S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:29])=[O:30])=[O:44]
Reactant: CN(C)C(=O)CBr
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)c2ccccc2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)cc2)cc1

Procedure:
Prepared analogously to Examples 1 and 187 from (Z)-1-acetyl-3-{1-[4-(p-tolylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSO and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH:19](Br)[CH3:20]>CN(C)C=O.O>[Br:18][CH2:19][CH2:20][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2ccccc12
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2nnn1CCBr
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
To a solution of the compound 1,2,3-benzotriazin-4(3H)-one (500 mg) (commercially available) in dimethylformamide (13 ml) was added anhydrous potassium carbonate (2.8 g) and stirred for 20 minutes. To it was added dibromoethane (2 g) and stirred the reaction mixture first at room temperature for few minutes and then at 60° C. for 2 hours. The solid thus obtained was filtered and the filterate was concentrated under reduced pressure. The residue thus obtained was diluted with water and extracted with ethylacetate. The organic layer was separated, washed with water and brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (590 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)(=[O:3])[CH3:2].[Br:14]Br.O>C(O)(=O)C>[C:10]([C:8]1[NH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:9]=1[Br:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C(C)(C)C)[nH]n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1n[nH]c(C(C)(C)C)c1Br
Temperature: 60 °C
Yield: 80 %

Procedure:
4.5 g (0.025 mole) of 3-acetylamino-5-t-butylpyrazole prepared in Example 3 was dissolved in 20 ml of acetic acid, and 4.0 g of bromine was added dropwise thereto while stirring. The reaction solution was heated at 60° C. for one hour and then cooled. 50 ml of water was added to the resulting solution and allowed to stand, whereby crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 5.2 g of 5-t-butyl-4-bromo-3-acetylaminopyrazole. This product was recrystallized from methanol and found to have a melting point of 234° to 235° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[S:12][C:13]([CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)=[CH:14][N:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:22]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:13]4[S:12][C:11]([Cl:10])=[N:15][CH:14]=4)=[CH:25][CH:24]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(OCc2cnc(Cl)s2)cc1
Product: Clc1ncc(COc2ccc(-c3nc4cc(Br)cnc4[nH]3)cc2)s1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=2)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([F:40])=[C:25]([C:27]2[CH:36]=[C:35](B(O)O)[C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH:26]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([F:40])=[C:25]([C:27]2[CH:36]=[C:35]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH:12]=4)[CH:7]=3)[C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH:26]=1
Reactant: Brc1cncc(-c2cnn(CCN3CCCC3)c2)c1
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cnn(CCN4CCCC4)c3)c2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 40 h

Procedure:
A slurry of 161 mg (0.50 mmol) 3-bromo-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridine, 167 mg (0.55 mmol) 2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and 50.4 mg (0.6 mmol) sodium bicarbonate in 2 ml DMF and 0.5 ml water was heated at 80° C. under nitrogen. Then 7.0 mg (0.01 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 40 hours at 80° C. Water was added, the resulting precipitate was filtered off and washed with water. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-Chloro-2-fluoro-phenyl)-4-{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine as colourless crystals; HPLC-MS: 1.67 min, [M+H] 499.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[S:5][C:4]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[CH:2].[H][H]>CO.C1COCC1.[C].[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:1][CH3:2])=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=2[CH:11]=1
Reactant: [H][H]
Reactant: C#Cc1c(C(=O)OCC)sc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1sc2cc(N)ccc2c1CC

Procedure:
Ethyl 3-ethynyl-6-nitro-1-benzothiophene-2-carboxylate obtained in Example (183d) was dissolved in methanol (16 mL) and THF (24 ml). A 10% palladium-carbon catalyst (120 mg) was added, and the mixture was stirred in a hydrogen atmosphere throughout the day. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140-142° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[C:19]2[C:27]3[C:22](=[C:23]([O:28]C)[N:24]=[CH:25][CH:26]=3)[N:21]([CH3:30])[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2C2C3C=CNC(=O)C=3N(C)C=2)CC1>>[CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[C:19]2[C:27]3[CH:26]=[CH:25][NH:24][C:23](=[O:28])[C:22]=3[N:21]([CH3:30])[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CCCCC3)cn(C)c12
Agent: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NCC2CC2)c2cc[nH]c(=O)c21
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NCC2CCCCC2)c2cc[nH]c(=O)c21

Procedure:
The title compound was prepared according to the procedure in Example 44C substituting the product from Example 47A for the product from Example 44C (0.027 g, 53%). 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.64 (dd, J=8.70, 2.29 Hz, 1H) 7.44-7.46 (m, 2H) 6.93 (d, J=7.02 Hz, 1H) 6.83 (d, J=8.85 Hz, 1H) 6.24 (d, J=6.71 Hz, 1H) 4.12 (s, 3H) 3.09 (s, 3H) 3.06 (d, J=7.32 Hz, 2H) 2.10-2.17 (m, 1H) 1.61-1.69 (m, 2H) 1.51-1.58 (m, 2H) 1.44-1.50 (m, 4H) 1.15-1.24 (m, 2H). MS (ESI+) m/z 414 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>>[CH3:17][O:16][C:12]1[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])=[C:10]([F:9])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Clc1ccccc1Br
Product: COc1cccc(F)c1-c1ccccc1Cl
Yield: 28.7 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[O:10][N:9]=[C:8]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:27])[N:14]3[O:19]CC2C=CC=CC=2)[N:7]=1>C(Cl)Cl>[NH2:5][C:6]1[O:10][N:9]=[C:8]([C@@H:11]2[CH2:17][CH2:16][C@@H:15]3[CH2:18][N:12]2[C:13](=[O:27])[N:14]3[OH:19])[N:7]=1
Reactant: Nc1nc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1nc([C@@H]2CC[C@@H]3CN2C(=O)N3O)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
BCl3 (1M, 5.08 ml, 5.08 mmol) was added to a solution of (2S,5R)-2-(5-amino-1,2,4-oxadiazol-3-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (160 mg, 0.508 mmol) in dry DCM (8 mL) at −78° C. The mixture was stirred under N2 atmosphere at 0° C. for 2 hrs then, it was cooled to −78° C. and quenched with MeOH (1.0 mL). The solvent was removed by vacuum to afford (2S,5R)-2-(5-amino-1,2,4-oxadiazol-3-yl)-6-hydroxy-1,6-diaza-bicyclo[3.2.1]octan-7-one (110 mg) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 226 [M+H]+.