Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[CH:17]=1>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:29])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1.26 g (0.052 mol) of magnesium was put in a 100 mL three-necked flask to which a dropping funnel and a Dimroth condenser were connected, and the flask was evacuated. The magnesium was activated by 30 minutes of heating and stirring. After cooling to room temperature, the flask was placed under a nitrogen gas flow. 5 mL of diethyl ether and several drops of dibromoethane were added, and 11.65 g (0.050 mol) of 2-bromobiphenyl dissolved in 15 mL of diethyl ether was slowly delivered from the dropping funnel by drops into the mixture. After the dropping was complete, the mixture was refluxed for 3 hours and made into a Grignard reagent. 11.7 g (0.045 mol) of 2-bromo-9-fluorenone and 40 mL of diethyl ether were put in a 200 mL three-necked flask to which a dropping funnel and a Dimroth condenser were connected. To this reaction solution, the synthesized Grignard reagent was slowly delivered by drops from the dropping funnel. After the dropping was complete, the mixture was refluxed for 2 hours, and then stirred at room temperature for about 12 hours. After the reaction was complete, the solution was washed twice with saturated ammonia chloride solution. An aqueous layer was extracted twice with ethyl acetate and combined with an organic layer, and the solution was washed with a saturated saline solution. After drying with magnesium sulfate, suction filtration and concentration were conducted, and a solid of 9-(biphenyl-2-yl)-2-bromo-9-fluorenol was obtained, weighing 18.76 g in a yield of 90%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu]I.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:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
To a stirred solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1 g, 2.63 mmol, 1 eq.) in 20 ml dry THF “degassed” with N2, was added cyclopropylacetylene (70%, 0.996 g, 10.54 mmol, 4 eq.) followed by N-ethyldiisopropylamine (1.36 g, 10.54 mmol, 4 eq.), Copper(I) Iodide (0.025 g, 0.132 mmol, 0.05 eq.) and Tetrakis(triphenylphosphine)palladium (0.152 g, 0.132 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction mixture was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was evaporated. The residue was purified by chromatography on silica gel to give N-{[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.57 g, 60% yield, single stereoisomer) as a brown gum.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[N:35][CH:34]=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: OB(O)c1cncnc1
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cncnc3)nc12
Yield: 69.3 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 28 mg of pyrimidin-5-yl-5-boronic acid via General Procedure A to give 45.7 mg of 205. MS (Q1) 484.3 (M)+.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]([C:27]([Cl:29])=[O:28])[CH2:19]1>C(N(CC)CC)C>[ClH:29].[ClH:1].[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:27]([CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:17])[CH2:19]2)=[O:28])[CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CC(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CC(=O)c3ccccc32)C(CN2CCCC2)C1
Yield: 31.9 %

Procedure:
The procedure described in Example 24 was repeated, but using 3.21 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 6.9 ml of triethylamine and 4.5 g of 3-oxoindan-1-carbonyl chloride, to afford 1.45 g of the title compound, melting at 252°-255° C. (dec.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:11]=1.CN(C)P(=O)(N(C)C)N(C)C.O>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][Cl:3])[CH:11]=1
Reactant: OCCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: ClCCCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.31 ml of thionyl chloride was added under ice-cooling to a solution of 0.86 g of 4-[5-chloro-2-(2-phenylethoxy)phenyl]butanol and 4 ml of hexamethylphosphoric triamide in 20 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 ml), extracted with ethyl acetate, successively washed with water twice and a saturated aqueous solution of sodium hydrogencarbonate 4 times and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 0.91 g of crude 4-chloro-2-(4-chlorobutyl)-1-(2-phenylethoxy)benzene was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[CH3:19][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[CH3:19]
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate in THF (18 mL) was added methylmagnesium bromide (in ether, 3 M, 2.7 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours, then quenched with saturated aqueous NH4Cl, and extracted with Et2O. The combined extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated to give the tile compound for the next step.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[C:8]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O.CO>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:8]2[C:7]([CH2:5][OH:4])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1cccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncccc2CO)CC1
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 44.1 %

Procedure:
NaBH4 (0.6 g, 15.8 mmol, 5 eq.) was added to a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (1.0 g, 3.1 mmol, 1.0 eq.) in THF (40 mL), under nitrogen. This mixture was cooled to 0-5° C. and MeOH (8 mL) was added dropwise. The resulting solution was stirred for 2.5 hours at room temperature. The solution was diluted with EtOAc (50 mL), then washed with saturated NH4Cl (1×100 mL) and saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3-hydroxymethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4]-bipyridinyl-1′-carboxylic acid t-butyl ester (0.4 g) as a white solid. MS m/z: [M+H]+ calcd for C16H25N2O3, 293. found 293.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[CH2:38](I)[CH3:39]>>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH2:38][CH3:39])[S:27]([CH:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CCC2)C1=O
Reactant: CCI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC)S(=O)(=O)C2CCC2)C1=O

Procedure:
By the method of Example 290, Step A, N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide (Example 298, Step A) was treated with ethyl iodide to afford the title compound as a white foam. LCMS (ESI) m/z=591.2 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[C:8]1([CH2:14][N:15]2[CH2:19][CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[Cs+]>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>[CH3:7][C:4]1[S:3][C:2]([C:17]2[CH2:16][N:15]([CH2:14][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Reactant: Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCN(Cc3ccccc3)C2)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The title compound can be prepared through a coupling palladium mediated reaction, e.g. starting from 2-bromo-5-methylthiophene and 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole. For example, to a solution of 2-bromo-5-methylthiophene (1.3 eq.) in THF, 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (1 eq.), tetrakis(triphenylphosphine)palladium(0) (5% mol) and cesium fluoride (4 eq.) may be added at room temperature. The resulting mixture should be stirred at 80° C. for 1.5 hours. After cooling the solvent should be evaporated under reduced pressure and the residue partitioned between dichloromethane and sodium hydroxyde (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by flash chromatography to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mg].II.CN([CH:26]=[O:27])C.Cl>C1COCC1.ClCCl>[C:1]12([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH:26]=[O:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h

Procedure:
11.09 g (37 mmoles) of 2-(1-adamantyl)-4bromo anisole dissolved in 85 ml of THF are slowly added to 1 g of magnesium and an iodine crystal. At the beginning of the addition, the reaction mixture is heated until the reaction begins, then the remainder of the solution is added in a manner to maintain a regular reflux. This reaction mixture is heated at reflux for 30 minutes after the end of the addition at which point 2.70 g (37 mmoles) of dry DMF are added. The reaction mixture is then stirred for 30 minutes without heating and then-poured into 300 ml of mixture of 2N aqueous HCl and dichloromethane.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[N:16][OH:15]
Reactant: Cc1ccccc1C(=O)C(F)(F)F
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=NO)C(F)(F)F
Temperature: 0 °C
Yield: 66.4 %

Procedure:
3.7 g (0.020 mol) of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone are dissolved in 20 ml of ethanol at 80° C. To the solution are added dropwise 1.4 g (0.020 mol) of hydroxylammonium chloride and 2.7 g (0.033 mol) of sodium acetate dissolved in 10 ml of water. The reaction mixture is refluxed for 5 hours, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.7 g of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone oxime as a white solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A mixture of methyl 2-(7-hydroxy-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.4 g, 23.90 mmol) and phosphoryl trichloride (10.94 ml, 120 mmol) was refluxed for 4 h. Then, cooled, concentrated and the dark residue was taken up in EtOAc (500 mL) and stirred with ice-water for 30 min. Aqueous layer separated and organic layer washed with water (2×50 mL). The combine aqueous layers extracted with EtOAc (100 mL) and the combined organic layers washed with brine (100 mL), dried (Na2SO4/C), filtered and concentrated to give dark paste. Purification by flash column chromatography on silica gel using 5-20% EtOAc/Hex afforded methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (5.6 g, 15.14 mmol, 63.3% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.76-7.71 (m, 2H), 7.18 (d, J=7.6 Hz, 1H), 6.92 (s, 1H), 3.93 (s, 2H), 3.78 (s, 3H), 2.89-2.84 (m, 4H), 2.63 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=370.11.
Reaction SMILES: [C:1]1([C:7]2C3C=C4C(CCC4)=CC=3C[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][Li].[Si](C)(C)(Cl)Cl>C1COCC1>[CH2:1]=[CH2:2].[CH2:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)c2cc3c(cc2C1)CCC3
Agent: C[Si](C)(Cl)Cl
Agent: [Li][Li]
Solvent: C1CCOC1
Product: C=C
Product: C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1,2,3,5-Tetrahydro-7-phenyl-s-indacene, dilithium salt (12.2075 g, 0.05102 moles) in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (19.5010 g, 0.1511 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at room temperature overnight. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (15.1492 g, 91.1% yield).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1.C1COCC1.OO.[Li+].[OH-:46]>O>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:30][C:25]([CH2:24][C@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([OH:37])=[O:46])=[CH:26][CH:27]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate (1.20 g, 2.402 mmol) in a mixed solvent of THF (20 mL) and water (5 mL), a solution of aqueous H2O2 (0.960 mL, 9.61 mmol) and aqueous LiOH (4.80 ml, 4.80 mmol) is added at 0° C. during 5 minutes. After stirring for 1.5 hour, the reaction is quenched with saturated aqueous Na2SO3 (10 mL) at 0° C., and allowed to stir for 10 minutes at the same temperature. The reaction mixture is warmed up to ambient temperature while stirring for 0.5 hour. Then, saturated aqueous NaHCO3 and brine are added to the mixture. The product is extracted with ethyl acetate, washed with aqueous 1M HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc=75:25 to 0:100) to give (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (765 mg, 93%). HPLC retention time=1.63 minutes (condition D); MS=338.6 (m−1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 2.41 (A of ABX, Jab=16.67 Hz, Jax=4.55 Hz, 1 H) 2.52-2.67 (B of ABX, Jab=16.75 Hz, Jbx=8.45 Hz, 1 H) 2.74-2.89 (m, 1 H) 3.06-3.22 (m, 2 H) 7.22-7.29 (m, 2 H) 7.30-7.37 (m, 1 H) 7.43 (t, J=7.58 Hz, 2 H) 7.53 (d, J=8.1 Hz, 2 H) 7.57 (d, J=7.8 Hz, 2 H).
Reaction SMILES: Cl.C[C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[F:12][C:13]([F:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CC(C)(C)[C:23](=[O:27])CC#N>>[F:12][C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:4]2[CH:3]=[CH:8][C:7]([O:27][CH3:23])=[CH:6][CH:5]=2)[N:11]=1)([F:20])[CH3:19]
Reactant: Cc1ccc(NN)c(C)c1
Reactant: CC(F)(F)C(=O)CC#N
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: COc1ccc(-n2nc(C(C)(F)F)cc2N)cc1
Yield: 11 %

Procedure:
Following the procedure for Example 282A Step 1, substituting p-methoxyphenylhydrazine for 2,4-dimethylphenylhydrazine hydrochloride and 4,4-difluoro-3-oxopentanenitrile was substituted for 4,4-Dimethyl-3-oxopentanenitrile. Concentration and purification using silica gel chromatography eluting with EtOAc/hexanes (5-40%) afforded 3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine in 11% yield. LC-MS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.N[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].[C:20]([BH3-])#[N:21].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH2:7][NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]3[NH:21][CH2:20][C:1]3[CH:6]=[CH:5][C:4]4[O:9][CH2:10][O:11][C:3]=4[CH:2]=3)=[CH:5][C:4]=2[O:9]1
Reactant: NC1CCCCC1N
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CO
Product: c1cc2c(cc1CN[C@@H]1CCCC[C@H]1NCc1ccc3c(c1)OCO3)OCO2
Reaction time: 48 h
Yield: 30 %

Procedure:
To a solution of piperonal (0.8 g, 5.3 mmol) and 1,2-diaminocyclohexane (0.296 g, 2.6 mmol) in dry methanol (25 ml) was added sodium cyanoborohydride (0.38 g, 6 mmol) and the mixture stirred for 48 h. The mixture was filtered and the solvents removed in vacuo to give the crude product. Crystallization from methanol gave DC-0012B as an off-white crystalline solid (0.298 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.O.Cl[CH2:25]Cl>CN(C)C=O>[CH3:18][N:16]([CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH2:14][O:15][CH3:25])[CH3:17]
Reactant: ClCCl
Reactant: CN(C)C(CCO)C1(c2ccc(Cl)cc2)CCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-[1-(4-chlorophenyl)cyclobutyl]-3-dimethylaminopropan-1-ol (7.8 g) in dichloromethane (150 ml) and dimethylformamide (4 ml) was treated at 0° C. with a solution of thionyl chloride (14 ml) in dichloromethane (7 ml). The mixture was stirred at room temperature for 45 minutes, then heated at reflux for 15 hours, cooled, poured into water and washed with dichloromethane. The aqueous phase was basified and extracted with ether. The extract was evaporated and the residue was dissolved in methanol (50 ml) and treated with sodium methoxide (1 g). The solution was heated under reflux for 17 hours and then concentrated to about 10 ml and diluted with water to 150 ml. The aqueous solution was extracted with ether and the extracts back-extracted with 3N hydrochloric acid. The acidic extracts were basified and extracted with ether. The ethereal extracts were dried and evaporated to give an oil which was mixed with petroleum ether (b.p. 40-60) (20 ml). The resulting mixture was filtered and evaporated to give N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methoxypropylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)N2CCCCC2)c1Cl

Procedure:
2,6-Dichloro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) is added portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. of dry methylene chloride, and the mixture heated to reflux for 1.5 hrs. The solvent and excess amine are removed under reduced pressure and the residue dissolved in 15 ml. of 2N sodium hydroxide. The aqueous base solution is extracted (2 × 50 ml.) with ether and acidified with 6N hydrochloric acid. The precipitated gum is filtered, dried and allowed to crystallize in hexane, 1.1 g., m.p. 145°-150° C. A small sample is recrystallized from acetonitrile, m.p. 142°-145° C.