Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
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: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 2-methoxypyridin-4-ylboronic acid (0.31 g, 2.02 mmol), potassium carbonate (0.56 g, 4.03 mmol), Pd(PPh3)4 (0.23 g, 0.20 mmol), and toluene (4 mL) at 100° C. for 18 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline as an off-white solid. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][Br:18])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccccc3)ccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 54 g of 2-phenyl-6-methyl-quinoline, 68 g of N-bromosuccinimide and 1.5 g of dibenzoyl peroxide in 700 ml of carbon tetrachloride is kept for 18 hours under reflux. Thereafter the reaction mixture is cooled to room temperature and the precipitate is filtered off. The filter residue is rinsed with carbon tetrachloride. The filtrate is evaporated and the residue is dissolved in ethyl acetate. This solution is washed with water and sodium chloride solution, dried over sodium sulphate and evaporated. The residue is taken up in 1.8 litres of ether and the insoluble constituents are filtered off. Concentration of the solution yields 2-phenyl-6-bromomethyl-quinoline of melting point 126°-127°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[Li]CCCC.[CH:25](=[O:28])[CH2:26][CH3:27]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:25]([OH:28])[CH2:26][CH3:27]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF was added nBuLi and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119-120° C.1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65-1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[CH:27]=[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:25]=[CH:24][C:23]=3[O:34][CH:35]([CH3:37])[CH3:36])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][C:26]1[CH:25]=[CH:24][C:23]([O:34][CH:35]([CH3:37])[CH3:36])=[C:22]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[C:18]3[C:13]=2[CH2:12][NH:11][CH2:20][CH2:19]3)[CH:27]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(OC(C)C)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC(C)C)c(-c2ccc(F)c3c2CNCC3)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(5-ethoxycarbonylmethyl-2-isopropoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.65 g, 3.17 mmol, 1 eq.) in EtOH (15.5 mL) under N2, palladium on activated carbon (10 wt. %, 165 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 24 hours and further at 50° C. for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, AcOEt to (AcOEt+10% NEt3) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([O:11][CH2:12]C)=[O:10])=[CH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(C)o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C)o1
Yield: 107.1 %

Procedure:
A mixture of ethyl β-(5-methyl-2-furanyl)acrylate (8 g) in methanol (200 mL) and 1.5 g of 5% palladium on carbon was placed on a Paar hydrogenator and hydrogenated with H2. Palladium on carbon was filtered off by passing the reaction mixture through Super-Cel™ (filter agent) and the residue was washed with ethanol. The filtrate was concentrated in vacuo to yield 8 g of methyl 3-(5-methyl-2-furanyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-chlorophenoxy)phenyl)-3-(4-fluorobenzyloxy)propanamide (200 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[N:14][C:13]([C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:28])[C:24]([OH:26])=[O:25])=[O:21])=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(NC(=O)c1ccc(-c2ccc(Cl)nn2)cc1)C(=O)O
Reactant: Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1ccc(-c2ccc(Nc3cccc(Cl)c3)nn2)cc1)C(=O)O
Temperature: 100 °C

Procedure:
A 1-dram vial was charged with 3-chloroaniline (0.2 Ml, excess) and 2-[4-(6 chloro-pyridazin-3-yl)-benzoylamino]-2-methyl-propionic acid (0.75 g) as a solid. The vial was heated to 100° C. for 1.5 h. The crude reaction mixture was then dissolved in 2 Ml DMF and then purified by reverse-phase preparative HPLC to afford the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.47 (s, 6H), 7.03 (dd, J=7.45, 1.64 Hz, 1H), 7.28 (d, J=9.35 Hz, 1H), 7.36 (t, J=8.08 Hz, 1H), 7.56 (dd, J=8.34, 1.26 Hz, 1H), 7.99 (d, J=8.59 Hz, 2H), 8.12-8.19 (m, 4H), 8.52 (s, 1H), 9.71 (s, 1H); (M+H)+411.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1([C:13]2[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100.1 %

Procedure:
According to Scheme 1, step 1: a mixture of morpholine (67.85 g, 0.779 mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].[ClH:24].CCOC(C)=O>>[ClH:24].[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[O:6])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl 4-(3-fluoro-4-methylbenzoyl)piperazine-1-carboxylate (3.14 g, 9.74 mmol) and 4 M HCl-EtOAc was stirred at rt for 20 h. After removing the solvent, the residue was suspended in EtOAc, and the white precipitate was collected by filtration to give 1.97 g (78% yields) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1.CCCCCC>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 3.0 g of hexane, 2.0 g of toluene, 0.06 g of tetra-n-butylammonium bromide and 5.0 g of water was added 0.77 g of a 27% aqueous sodium hydroxide solution. The mixture was heated to 60° C. and stirred for 4 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 93%, yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][PH:21](=[O:25])[O:22][CH2:23][CH3:24]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]([P:21]([CH3:20])(=[O:25])[O:22][CH2:23][CH3:24])[OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccc(Cl)cc1
Reactant: CCO[PH](C)=O
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1.46 g of 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde, 0.54 g of ethyl methylphosphinate and 0.695 ml of triethylamine is heated to 100° for 2 hours. The reaction mixture is cooled to room temperature and chromatographed on silica gel to give ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxypropyl(methyl)phosphinate.
Reaction SMILES: [OH-].[K+].Cl.[CH3:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl>O.C1COCC1.C(Cl)Cl>[CH3:4][N:5]([S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=1)(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CNCCCC(=O)O
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(CCCC(=O)O)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of KOH (16.5 g, 294 mmol) in H2O (75 ml) was added 4-(methylamino)butyric acid hydrochloride (10, 15.1 g, 98.1 mmol) and the reaction mixture was cooled with an icebath. A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (9, 12.0 g, 49.1 mmol) in THF (75 ml) was dropwise added to the reaction mixture and stirring was continued at room temperature overnight. Aqueous 6 M HCl (75 ml) was added to the reaction mixture while cooling with an icebath, after which CH2Cl2 was added. The organic layer was separated, washed with brine, dried (Na2SO4), concentrated and co-evaporated with a minimal amount of Et2O. Crystallization of the residue out of EtOAc/heptane resulted in AC-08 (11.32 g, 71%).
Reaction SMILES: Cl.Cl[Sn]Cl.O.[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[C:16]([N+:26]([O-])=O)=[C:17]2[S:25][CH2:24][CH2:23][N:18]2[C:19](=[O:22])[C:20]=1[CH3:21].C(=O)(O)[O-]>C(O)C.C(Cl)Cl.C(OC(=O)C)C>[NH2:26][C:16]1[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:20]([CH3:21])[C:19](=[O:22])[N:18]2[CH2:23][CH2:24][S:25][C:17]=12
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Temperature: 25 °C
Yield: 98 %

Procedure:
Concentrated HCl (0.3 mL) and SnCl2.H2O (0.15 g, 0.671 mmol) were added to 7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.1 g, 0.22 mmol) in ethanol (3 mL). The resulting mixture was heated to reflux for 2 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was cooled to room temperature, diluted with DCM, basified with saturated bicarbonate solution and filtered through celite. The filtrate was extracted with DCM. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 0.09 g of the product (90% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[CH:6][C:5]([C:21]#[C:22][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:21]([C:5]1[CH:6]=[C:7]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)[C:2]([F:1])=[N:3][CH:4]=1)#[CH:22]
Reactant: C[Si](C)(C)C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Yield: 87 %

Procedure:
To a 25 mL round bottom flask was added (4R,5R)-4-(2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (77 mg, 0.207 mmol) in MeOH (4 mL). The solution was stirred and potassium carbonate (28.6 mg, 0.207 mmol) was added in one portion and the reaction was allowed to stir for 30 min. The reaction was complete by TLC and LC/MS. The reaction solvent was then evaporated in vacuo and the crude solid was dissolved in dichloromethane and washed with saturated ammonium chloride. The organic layer was separated, dried over sodium sulfate, and evaporated in vacuo to afford (4R,5R)-4-(5-ethynyl-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (60 mg, 0.180 mmol, 87% yield) as an off white solid. This material was used as is without purification. 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.07 (dd, J=8.0, 2.0, 1H), 7.47-7.42 (m, 1H), 7.19-7.12 (m, 3H), 5.86 (brs, 1H), 5.37 (d, J=4.0, 1H), 5.02 (s, J=4.0, 1H), 3.31 (s, 1H). LC/Mass spec. (Analytical HPLC method 2): RT=1.82 min. Mass=301.19 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:17])=[N:4][CH:3]=1.[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([S:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:24])=[O:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][C:11]=2[F:17])=[N:4][CH:3]=1
Reactant: N#Cc1nc(N)cnc1-c1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 6-amino-3-(4-bromo-2-fluorophenyl)pyrazine-2-carbonitrile and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for O21H20FN5O2S, 425.13; m/z found, 426.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 7.64-7.56 (m, 2H), 7.54-7.49 (m, 1H), 7.47 (dd, J=7.9, 1.7, 1H), 7.40-7.33 (m, 2H), 1.04 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17]O)[CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1>C(Cl)Cl>[Br:48][CH2:17][C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: COCCCn1ncc2ccc(C[C@@H](CO)C(C)C)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCn1ncc2ccc(C[C@@H](CBr)C(C)C)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of (R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutan-1-ol (100 mg, 0.3 mmol) in dry CH2Cl2 (3 mL) at 0° C., Ph3P (140 mg, 0.6 mmol) and NBS (95 mg, 0.6 mmol) were added in portions. After stirring for 12 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to afford (R)-6-(2-(bromomethyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (70 mg, 62%). 1H NMR (400 MHz, CDCl3): 1.02 (m, 6H), 1.74 (m, 1H), 1.89 (m, 1H), 2.17 (m, 2H), 2.71 (m, 1H), 2.95 (m, 1H), 3.32 (s, 3H), 3.43 (m, 1H), 4.45 (m, 2H), 6.98 (d, 1H), 7.27 (s, 1H), 7.63 (d, 1H), 7.95 (s, 1H); MS: 432 (M++1)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH:5]1[N:9]([CH3:8])[C:10](=[S:13])[N:11]=[N:12]1)[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC1N=NC(=S)N1C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Ethoxyacetyl chloride (57 g) was added slowly to a stirred solution of 4-methylthiosemicarbazide (53.5 g) in dry pyridine (500 ml) at 0-5°. The mixture was allowed to attain room temperature and stirring was continued for 18 hours. Following concentration under reduced pressure the residue was treated with a solution of sodium (21.4 g) in ethanol (500 ml) and the mixture was heated under reflux for 24 hours. Following concentration and acidification with hydrochloric acid a solid was obtained. After partial concentration the solid was collected and recrystallised from ethyl acetate to give 3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g) m.p. 137°-138°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]=O)[CH:7]=[N:6]2.CO.ClCCCl.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+]>>[CH:23]1([NH:29][CH2:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2ncc(C=O)nc2cc1OC
Reactant: NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cc2ncc(CNC3CCCCC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2:1 MeOH/1,2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine (0.11 mL, 0.9 mmol). The reaction is allowed to stir at room temperature overnight, then NaBH4 (0.038 g, 1 mmol) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc/hexanes-approximately 5% MeOH in 50% EtOAc/hexanes). The oil is dissolved in EtOAc/hexanes and treated with HCl in EtOH. The resulting solution is concentrated and the solids are triturated with isopropanol to provide a white solid after drying in vacuo at 60° C. (m.p. 185-190° C., dec.). Anal. Calcd. for C17H23N3O2 • HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07.
Reaction SMILES: Br[C:2]1[S:25][C:5]2[N:6]=[C:7]([N:10]3[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:12][CH2:11]3)[N:8]=[CH:9][C:4]=2[C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]([NH2:35])(=[O:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC#N>[C:26]1([C:3]2[C:4]3[CH:9]=[N:8][C:7]([N:10]4[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:18][CH2:19][N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[CH2:12][CH2:11]4)=[N:6][C:5]=3[S:25][C:2]=2[NH:35][C:32](=[O:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(N)=O
Reactant: Brc1sc2nc(N3CCC(COCCN4CCCC4)CC3)ncc2c1-c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)Nc1sc2nc(N3CCC(COCCN4CCCC4)CC3)ncc2c1-c1ccccc1
Temperature: 150 °C
Yield: 18.3 %

Procedure:
6-Bromo-5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (0.125 g, 0.25 mmol), acetamide (0.022 g, 0.37 mmol), cesium carbonate (0.163 g, 0.5 mmol), xantphos (0.022 g, mol %), Pd2(dba)3 (0.010 g, 5 mol %) and MeCN (2 mL) were combined and heated to 150° C. for 30 minutes. The reaction was diluted with DCM (10 mL), washed with water (10 mL), passed through a hydrophobic frit and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC to afford N-[5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]acetamide (22 mg). LCMS [M+H]+=480.2
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)nc1
Yield: 83.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (5-bromopyridin-2-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2.4 g) described in Preparation Example 35 and (R)-4-methyloxazolidin-2-one (728 mg) described in Preparation Example 25, the title compound (2.1 g) was obtained.