Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[Cl:24][C:22]1[CH:23]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:8]2[CH:21]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(OC)cc2)c1=O
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)c3cc(Cl)cn32)cc1

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-methoxy-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 406 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)C>[C:24]1(=[N:23][NH:22][C:20](=[O:21])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: O=C1CCCC1
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=C2CCCC2)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.40 g, 0.0012 mol) was mixed cyclopentanone (1.0 g, 0.0012×10 mol) and then with diethyl ether (about 10 ml). The resultant mixture was stirred at room temperature for about one hour. The obtained reaction solution was concentrated, thereby obtaining an aimed product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3ncn(C)c(=O)c23)cc1
Temperature: 110 °C

Procedure:
5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C, 125 mg, 0.60 mmol, 1 eq), p-toluenesulfonyl chloride (138 mg, 0.72 mmol, 1.2 eq) and triethylamine (126 μl, 0.90 mmol, 1.5 eq) were dissolved in acetonitrile (2 ml). The mixture was heated at reflux (oil bath at 110° C.) for 3 hours to yield 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate (compound 1D). The product was confirm by LC-MS. Solvent was removed in vacuo and the crude product 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonateused in the following reaction.
Reaction SMILES: [OH:1][C@@H:2]([CH2:32][OH:33])[CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:1][C@@H:2]([CH2:32][OH:33])[CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:35]\[OH:36])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((R)-2,3-dihydroxypropyl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=464.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Yield: 47 %

Procedure:
A solution of 16.20 g (0.05 mole) of the benzylidene hydantoin from Example 4 in 100 mL of methanol and 25.0 g (0. 055 mole) of 20% tetramethylammonium hydroxide-in-methanol is reduced with hydrogen and Raney nickel catalyst. After the theoretical uptake of hydrogen the mixture is filtered and acetic acid (ca 5 mL) and then water is added until just turbid. The first crop of solid is filtered. This is starting material. An additional 2 L of water is added to precipitate the product as crop 2; wt 7.60 g (47% yield). Recrystallization from methanol gives pure product; mp 155°-157° C. Anal. Calc. for C18H18N2O4 : C, 66.24; H, 5.56; N, 8.59. Found: C, 66.19; H, 5.60; N, 8.68.
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1.COC(CC)CC#N>O.ClCCl>[NH2:5][C:6]1[CH2:10][CH:9]([CH2:2][CH3:3])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1
Reactant: CCO
Reactant: NC1=NN(c2cccc(Cl)n2)CC1
Agent: CCC(CC#N)OC
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CCC1CC(N)=NN1c1cccc(Cl)n1

Procedure:
A 0.26 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 8.1 g. of 2-chloro-6-hydrazinopyridine (Example 2) is added followed by 6.4 g. of 3-methoxyvaleronitrile. The reaction mixture is refluxed for 16 hours, then is evaporated in vacuo to give a solid. The solid is dissolved in water/dichloromethane. The organic layer is separated, dried over magnesium sulfate, filtered through anhydrous magnesium silicate and concentrated while adding hexane to yield 7.0 g. of pale yellow crystals. A 200 mg. amount of the crude product is recrystallized from dichloromethanehexane to give 171 mg. of the product of the Example, as pale yellow crystals, m.p. 131°-133° C.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=CC(/C=C/C1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[N:46]=[CH:47][NH:48][CH:49]=1.I[C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[C:54]#[N:55]>C1(C)C(C)=CC=CC=1.ClCCl>[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[N:46]=[CH:47][N:48]([C:51]2[CH:58]=[CH:57][CH:56]=[C:53]([C:54]#[N:55])[CH:52]=2)[CH:49]=1
Reactant: c1ccc(-c2c[nH]cn2)nc1
Reactant: N#Cc1cccc(I)c1
Agent: O=C(C=Cc1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: N#Cc1cccc(-n2cnc(-c3ccccn3)c2)c1
Temperature: 120 °C
Yield: 8.3 %

Procedure:
To a flame dried, argon purged screw-cap vial, containing copper (I) triflate.benzene complex (0.01 g, 0.03 mmol), 1,10-phenanthroline (0.10 g, 0.54 mmol), trans-dibenzylideneacetone (0.01 g, 0.03 mmol) and cesium carbonate (0.20g, 0.60 mmol) was added a solution of 4-(2-pyridyl)imidazole (0.08 g, 0.54 mmol) and 3-iodobenzonitrile (0.19 g, 0.82 mmol) in ortho-xylene (2 mL). The resulting brownish black reaction mixture was heated overnight at 120° C. After cooling, the reaction mixture was diluted with dichloromethane (20 mL) and washed sequentially with saturated ammonium chloride (20 mL) and brine (20 mL). The organic phase was then dried with sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the crude residue using 1% methanol (2 M in ammonia) in dichloromethane afforded 11 mg of 4-(2-pyridyl)-1-(3-cyanophenyl)-1H-imidazole, as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[CH:18]=2)O)=[C:13]([CH3:25])[CH:12]=[C:11]([CH3:26])[N:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[CH3:23])[CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:26])=[CH:12][C:13]=1[CH3:25]
Reactant: Cc1cc(C)c(C(O)c2ccc(C)c(F)c2)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(Cc2ccc(C)c(F)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 2-benzyloxy-4,6-dimethylpyridin-3-yl 3-fluoro-4-methylphenyl methanol (0.39 g) in ethanol (10 mL) was added a catalytic amount of palladium carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After the insoluble material was removed by filtration, the solvent of the filtrate was removed to give the title compound (0.22 g).
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][CH:3]=[CH:2]2.[Br:9]Br.S([O-])([O-])=O.[Na+].[Na+]>O.CCCCCC>[Br:9][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][C:1]=2[CH:2]=1
Reactant: c1ccc2c(c1)CC2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Brc1ccc2c(c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bicyclo[4.2.0]octa-1(6),2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature. Upon cooling by an ice-water, 3.9 mL of bromine was added dropwise. Upon completion of the addition, the ice-water bath was removed and the reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of n-hexane and sodium sulfite (3 g, 23.8 mmol) was added. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. Then the separated organic layer was dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 3-bromo-bicyclo[4.2.0]octa-1(6),2,4-triene 5b (13.53 g) as a colourless oil, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-trifluoromethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:29]([CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[CH2:2][N:35]4[CH:36]=[C:32]([CH2:31][C:29]#[N:30])[N:33]=[CH:34]4)[CH:15]=[CH:14][N:13]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: N#CCc1c[nH]cn1
Reactant: BrCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCc1cn(Cc2cccc(Sc3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred mixture of 4-(3-(bromomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (100 mg, 0.22 mmol) and 4-cyanomethyl imidazole (47 mg, 0.44 mmol) in dimethyl formamide (2 mL), was added cesium carbonate (154 mg, 0.44 mmol) in one portion. The mixture was stirred at room temperature for 16 hours. It was filtered to remove any inorganic material, and the dimethyl formamide solution was concentrated in vacuo. The residue was column chromatographed on the silica gel using methanol:dichloromethane (4:96) as eluant to give the product (50 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]\[CH2:18]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:38].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]/[CH2:18][I:38])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of diphenylmethyl 7-t-butoxycarbonylamino-3- [(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IIIa) (541 mg, 1 mmol) and sodium iodide (450 mg, 3 mmol) in acetone (5.4 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml), washed with aqueous sodium thiosulfate and water successively, dried with MgSO4 and concentrated to yield 632 mg of the title product.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][C:8]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.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]>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:19]=[C:18]3[C:5]([CH2:6][CH2:7][C:8]4([C:11]53[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]5)[CH2:9][CH2:10]4)=[CH:4][CH:3]=2)[CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1=NC2(N=C1N)c1cc(-c3cncc(Cl)c3)ccc1CCC21CC1
Temperature: 130 °C
Yield: 37.7 %

Procedure:
A mixture of 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 100 mg, 0.31 mmol), 5-chloropyridin-3-ylboronic acid (74 mg, 0.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (23 mg, 0.03 mmol), aq. potassium carbonate (2 M, 0.31 mL, 0.63 mmol) and 1,4-dioxane (1 mL) were mixed in a vial and heated in a microwave reactor at 130° C. for 30 min. When cooled to r.t., the mixture was diluted with DCM, washed with water and dried over Na2SO4. The filtrate was concentrated and the product purified by preparative HPLC to give the title compound (41 mg, 37% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.10 (m, 2 H), 0.24 (m, 1 H), 0.55 (m, 1 H), 1.51 (dt, 1 H), 2.18 (s, 3 H), 2.39 (m, 1 H), 3.01 (m, 2 H), 6.52 (br. s., 2 H), 6.74 (d, 1 H), 7.30 (d, 1 H), 7.52 (dd, 1 H), 7.97 (s, 1 H), 8.57 (d, 1 H), 8.61 (d, 1 H); MS (APCI+) m/z 351 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1CCCCC1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclohexanone (98 mg, 1.00 mmol, 1.51 equiv) and acetic acid (120 mg, 2.00 mmol, 3.03 equiv) in 1,2-dichloroethane (10 mL) was stirred for 4 h at room temperature. To this was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified on a silica gel column with water/acetonitrile (95/5-20/80) to give 350 mg (99%) of 4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 537 [M+H]+; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 8.00 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.40 (s, 2H), 3.14 (d, 3H), 2.50 (d, 3H), 2.41-2.33 (m, 3H), 2.25 (d, 2H), 1.92-1.83 (m, 6H), 1.67 (d, 1H), 1.29-1.09 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([O:12]C)=[O:11])[CH:7]=1.[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:21][CH2:23][CH2:22][O:24][CH2:25][CH3:26])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Reactant: CCOCCBr
Solvent: CCOCC
Product: CCCCCC(CC(=O)O)c1cc(Cl)c(OCCOCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45a-(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 56A) and 2-ethoxyethyl bromide, the corresponding. ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:22][N:23]([CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH2:8][OH:10])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNCCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: CN(CCc1ccccc1)Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared using intermediate 44 and N-methylphenethylamine.
Reaction SMILES: [C:1]([C:5]1[C:15]([F:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=1)[CH3:30]>C(N(CC)CC)C>[C:1]([C:5]1[C:6]([F:17])=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:28][C@@H:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH3:30])=[O:13])=[CH:14][C:15]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)cc1
Yield: 63.2 %

Procedure:
((4-tert-Butyl-3,5-difluorophenoxy)acetic acid (147 mg, 0.60 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (102 mg, 0.63 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]phenyl}methanesulfonamide hydrochloride (150 mg, 0.60 mmol) were mixed by the same procedure as described in Example 1(e) to give 167 mg (63%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[CH:21]=[CH:20][S:19][C:18]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:20]1[S:19][C:18]([CH3:22])=[C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3ccsc3C)c(C)nc12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3cc(Br)sc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine. (0.76 g, 2.42 mmol) and CH2Cl2 (10 mL) is added NBS (0.60 g, 3.37 mmol). The solution is stirred at ambient temperature for 2 hours and concentrated. The solution is dissolved in Et2O (30 mL) washed with water (3×30 mL), brine (30 mL) dried over MgSO4, filtered and concentrated to furnish the title compound (0.95 g, 2.42 mmol, >99%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.93 (m, 4H), 2.31 (s, 3H), 2.42 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.04 (s, 1H). LC/MS (m/z): calcd. for C18H22BrN3S (M+H)+: 392.2; found: 392.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.[C:21]([Mg]Br)#[CH:22]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Yield: 106.9 %

Procedure:
5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.90 g, 3.14 mmol) in tetrahydrofuran (50 mL) was treated with ethynylmagnesium bromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) as described in Example 12 to give 1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (1.05 g, 100%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.05 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s, 3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (4) (0.021 g, 0.043 mmol) in anhydrous methanol (2 mL) were added a 37% aq. solution of formaldehyde (0.006 g, 0.195 mmol) followed by sodium triacetoxyborohydride (0.046 g, 0.217 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 1 hour, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (5) (20 mg, 93% yield) as a an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.30-7.15 (m, 6H), 3.67 (s, 2H), 3.19-3.12 (m, 2H), 3.12-3.02 (m, 2H), 2.96 (d, J=11.1 Hz, 2H), 2.85-2.74 (m, 1H), 2.34 (s, 3H), 2.13-2.03 (m, 2H), 1.96-1.67 (m, 3H), 1.49 (ddd, J=24.8, 12.5, 3.9 Hz, 1H). LCMS Method C: rt 4.86 min; m/z 498.3 [M+H]+.