Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6]N=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li][CH2:12]CCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])C(=O)OC(C)(C)C)=[CH:19][CH:18]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:32][CH2:33][O:34][CH3:35])=[CH:19][CH:18]=3)=[CH:8][C:4]=2[CH:12]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2ccsc12
Reactant: [Li]CCCC
Reactant: COCCN(Cc1ccc(Br)nc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCNCc1ccc(-c2cc3cccc(Cl)c3s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine 6 (7.37 g, 43.4 mmol, 1.5 eq) in THF (70 mL) at −10° C. in a 250 mL round-bottom flask was added n-BuLi (17.38 mL, 43.4 mmol, 1.5 eq). After 1 h, ZnCl2 (1M in ether) (43.4 mL, 43.4 mmol, 1.5 eq) was added at −10° C. and the reaction mixture was allowed to warm up to r.t. After 1 h, Pd(PPh3)4 (0.669 g, 0.579 mmol, 0.02 eq) and bromide 10 (10 g, 29 mmol, 1 eq) in THF (10.5 mL) were added and the mixture was heated to reflux for 1 h. After cooling to room temperature the reaction mixture was concentrated to dryness. DCM (200 mL)/water (160 mL)/NH4OH (40 mL) were added to the solid and the resultant mixture (an emulsion) was stirred for 1 h. Brine (50 ml) was added to the emulsion and the stirring was continued for an additional 10 min. The mixture was then filtered through a paper filter and phases were separated. The aqueous phase was extracted with DCM (2×50 mL). The organic phases were combined, dried over Na2SO4 and concentrated to dryness. MTBE (30 mL) was added to the solid and the suspension was stirred for 30 min. The solid was collected by filtration, washed with MTBE (2×5 mL) and dried to afford of 11 as a beige solid (8.02 g, 64% yield). MS (m/z): 434.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:26])(=O)=O>>[CH3:26][N:9]1[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[C:20](=[O:21])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Product: Cn1c2c(cnc3ccccc32)c(=O)n1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The mixture of 3.0 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and 100 ml of dimethyl sulfate is stirred at 110°-130° for 2 hours and evaporated. The residue is dissolved in N aqueous sodium hydroxide, the solution extracted with methylene chloride and the extract evaporated. The residue is recrystallized from diethyl ether, to yield the 1-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 158°-161°.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][CH:8]=[CH:9][NH:10][CH:5]2[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])Br.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][O:12][C:13]([C@@H:14]([N:10]1[CH2:9][C:8]2[CH:7]=[CH:6][S:2][C:3]=2[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:23]
Reactant: C1=CNC2CCSC2=C1
Reactant: COC(=O)C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 82.5 °C

Procedure:
50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted with 83 g (0.315 mole) of α-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5 Lt. DMF in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 Hrs. The reaction mixture was filtered at RT and washed the residue with DMF. The DMF was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the base was extracted from the aqueous layer using methylene dichloride. The methylene dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =92%
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[O:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=O)[CH2:17][CH2:16]1.C([O-])(=O)C.[NH4+:30]>C1(C)C=CC=CC=1>[NH2:9][CH2:8][C:5]1[C:6]([NH2:30])=[N:7][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][CH2:16][C:17]=2[C:4]=1[C:3]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1]
Reactant: [NH4+]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: NCc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)COc1ccccc1-2
Temperature: 118 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
2-(2,4-dichloro-benzylidene)-malononitrile (95 mg, 0.4 mmol), chroman-4-one (59 mg, 0.4 mmol), ammonium acetate (78 mg, 1.2 mmol), and toluene (4 ml) were placed in a reaction vial and shaken overnight at 118° C. Upon cooling and filtration, the solution was evaporated in a vacuum zentrifuge (45° C.) and the residue was purified by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA (aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min). The obtained solid (28 mg) was dissolved in THF (1 ml) and added, under an atmosphere of Argon, to a cooled (0° C.) suspension of 100 mg of Lithium aluminum hydride in 1 ml THF in a reaction vial. The reaction mixture was shaken first for 2 h at r.t. and subsequently for 4 h at 40° C. Upon cooling, water was added carefully and the mixture was filtered. The filtrate was evaporated in a vacuum zentrifuge (45° C.). Purification of the re-dissolved (DMF, 1 ml) residue by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) gave 11 mg (7%) of the title compound, MS: m/e=371.9 (M+H+), as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=O)=[CH:13][N:12]=1)[CH2:9][CH3:10].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:19])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxamide (example 4) (1.0 g, 2.85 mmol) was suspended in tetrahydrofuran (15 ml) and the stirred solution treated with pyridine (0.46 ml, 0.46 g, 5.7 mmol) and trifluoroacetic anhydride (0.9 ml, 1.35 g, 6.4 mmol) at ambient temperature (slight exotherm). A yellow colour became apparent and the solid dissolved in the THF. The solution was left standing at ambient temperature overnight, then further pyridine (0.46 ml, 5.7 mmol) and TFAA (0.90 ml, 6.4 mmol) were added and the reaction was again left overnight. The mixture was evaporated to low volume, saturated sodium bicarbonate solution was added and the mixture stirred at ambient temperature for 30 minutes, evaporated to low volume and the resultant white precipitate filtered, washed with water and air dried to give 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-cyanopyridine as a white solid (1.0 g, 100%).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[N+](C1C=CC([C:17]2[C:25]([CH2:26][C@H:27]3[C@@H:32]([OH:33])[C:31]4[CH:34]=[C:35]([O:38][CH2:39][C:40]5[S:41][C:42]6[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:43]=6[N:44]=5)[CH:36]=[CH:37][C:30]=4[O:29][CH2:28]3)=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([O-])=[O:20])=CC=1)([O-])=O.C(OC(Cl)=O)C(C)C>O1CCCC1>[F:49][C:46]1[CH:47]=[CH:48][C:42]2[S:41][C:40]([CH2:39][O:38][C:35]3[CH:36]=[CH:37][C:30]4[O:29][CH2:28][C@@H:27]([CH2:26][C:25]5[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=5)[C:19]([N:3]([CH3:4])[CH3:1])=[O:20])[C@@H:32]([OH:33])[C:31]=4[CH:34]=3)=[N:44][C:43]=2[CH:45]=1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
364 milligrams triethylamine was added to a solution containing 1.5 grams cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate in tetrahydrofuran at 0° C. After stirring for 5 minutes at 0° C., a solution of isobutylchloroformate in 5 milliliters of tetrahydrofuran was added dropwise. After stirring at 1° C. for 15 minutes, 364 milligrams anhydrous dimethylamine was bubbled into the reaction mixture for 1-2 minutes. The reaction mixture was allowed to warm to room temperature and the volatiles were evaporated. The residue was purified by chromatography on silica gel eluting with methylene dichloride/ethyl acetate to give 535 mg of product.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH:15]2[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+].CCO>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CC1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of tetrahydrofuran. To the stirred solvent was added ethyl 2-(4-methoxyphenyl)cyclopropanecarboxylate (8 g, 36 mmol). The reaction mixture was cooled to 0° C. and sodium hydroxide (2.1 g, 54 mmol) in water (5 mL) was added drop wise, followed by ethanol (10 mL). The reaction mixture was stirred for 8 h at room temperature. The reaction mixture was concentrated to distill off the solvent; the crude was acidified with 1N hydrochloric acid to make acidic pH and extracted with ethyl acetate (50 mL). The layers were separated; the organic layer was washed with brine solution (20 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as off white solid (6.5 g, yield: 94.2%). 1H NMR (300 MHz, CDCl3): δ 6.96-6.99 (d, 2H), 6.74-6.77 (d, 2H), 3.71 (s, 3H), 2.46-2.53 (m, 1H), 1.72-1.78 (m, 1H), 1.52-1.58 (m, 1H), 1.27-1.32 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[C:9]=2[CH:18]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:18]=1)=[O:4]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COC(=O)c1ccc2nnn(CCCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole (9.61 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.8 g compound (I-56) with a yield of 63.4%. ESI-MS [M+H]+: m/z 461.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:40][N:41](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:40][NH:41][C:33]([C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1)=[O:34]
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A DMF solution (3 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (260 mg, 0.56 mmol) and methylamine hydrochloride (379 mg, 5.6 mmol) in a sealed tube was charged with DIEA (0.98 mL, 5.6 mmol), 0.6M HOAt in DMF (0.93 mL, 0.56 mmol), and then EDC (161 mg, 0.84 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2% ˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from MeOH/CH2Cl2/diethyl ether to the desired product as a light yellow solid; 1H NMR (DMSO-d6, 400MHz) δ 1.56-1.73 (m, 4H), 1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H), 2.52 (d, 3H, J=4.4 Hz), 3.12-3.20 (m, 1H), 6.17 (s, 2H), 7.09 (d, 1H, J=4.8 Hz), 7.51-7.59 (m, 4H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.30 (d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 477.0 [MH+]; HPLC: tR=2.1 min (Micromass Platform II, polar—5 min).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].Cl[C:20]1[N:25]=[C:24](Cl)[C:23]([F:27])=[CH:22][N:21]=1>CCOCC>[CH2:1]([O:17][C:20]1[N:25]=[C:24]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23]([F:27])=[CH:22][N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOc1ncc(F)c(OCCCCCCCCCCCCCCCC)n1
Yield: 63.1 %

Procedure:
A 36.3 g quantity of n-hexadecanol is dissolved in 200 ml of absolute ether, 3.3 g of metal sodium is added to the solution and the mixture is refluxed until the sodium has been completely dissolved. Subsequently 8.5 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution, and the mixture is refluxed for 3 hours. The resulting reaction mixture is washed with a small amount of water, and the ethereal layer is concentrated to separate out crystals, which are recrystallized from ethanol to give 18.6 g of white crystalline 2,4-di(n-hexadecyloxy)-5-fluoropyrimidine in a yield of 63.1%, m.p. 62°-63° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](I)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:25]3[C:21]([CH3:20])=[N:22][O:23][C:24]=3[CH3:35])[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCCI
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(C)noc2C)c2c(c1)[nH]c(=O)n2C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (40 mg, 0.11 mmol, 1 equiv.) were added 3,5-dimethylisoxazole-4-boronic acid pinacol ester (72 mg, 0.32 mmol, 3 equiv.), Cs2CO3 (141 mg, 0.43 mmol, 4 equiv.), PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) and DME-H2O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. After 1 hr, the reaction was complete. Following cooling, the reaction mixture was extracted with EtOAc and the organic solution was washed with water, saturated NH4Cl. After drying with MgSO4, it was filtered and concentrated to dryness. The resulting solid was washed with EtOAc. Purification of the residue was carried out by reverse phase HPLC to furnish the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12].N1C=CC=CC=1>C(OCC)(=O)C>[C:5]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([Cl:8])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C)c(Cl)c1
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
Acetic anhydride (78 ml, 0.825 mol) was added in portions (using a dropping funnel) during a 45 min period to a stirred, cooled in an ice-bath solution of 3-chloro-4-methylaniline (106.2 g, 0.75 mol) in ethyl acetate (550 ml, dried over MgSO4 prior to use) and anhydrous pyridine (66.6 ml, 0.825 mol) under argon. During the reaction the temperature of the reaction mixture varied between 10-20° C. Stirring was continued for 20 min; then the ice-water bath was removed and the reaction mixture was stirred for 18 h at room temperature. The solvents were removed in vacuo and the light brown solid residue was triturated with ether (350 ml) and left to stand in a fridge overnight. The solid was collected by filtration, washed with cold ether (100 ml) and hexanes (100 mL), dried over P2O5 to afford a white solid (90 g). The filtrate was concentrated in vacuo, triturated with ether to afford an additional 28.1 g of the product. Total yield 118.1 g (86%); mp 105-106° C.; 1H-NMR (CDCl3) 2.17, 2.32 (2×s, 6H, 4-CH3, CH3CO), 7.14 (d, J=8.22 Hz, 1H, 6-H), 7.25 (2×dd, J=1.9, 6.5 Hz, 1H, 5-H), 7.58 (d, J=1.8 Hz, 1H, 3-H); MS (FAB, m/z) 184, 186 [(M+H)+ 100%, 30% respectively; Cl isotopic pattern].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:46]([O:50][C:51]([NH:53][C@@H:54]([CH2:57][S:58][C:59]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)C=O)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl.ClC(Cl)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:54]([NH:53][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:57][S:58][C:59]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(Cc2ccccc2)CCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
4-Benzyl-1-tert-butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine from Example 7, step C (1.17 g, 3.50 mmol) was dissolved in methylene chloride (20 mL). To this solution was added trifluoroacetic acid (10 mL) and the reaction stirred at 20° C. for 1 h. The volatiles were removed in vacuo and the residue taken up in dichloroethane (40 mL). Triethylamine was added to attain pH 7. To this solution was added crushed molecular seives (1 g), sodium triacetoxyborohydride (1.2 g, 5.3 mmol) and the reaction cooled to -15° C. with ice-methanol. A solution of 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropanal (1.72 g, 3.85 mmol) in dichloroethane (15 mL) was added slowly dropwise. The reaction was stirred at 20° C. overnight then quenched with saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution, and dried over magnesium sulfate. The crude product (2.52 g) was chromatographed on silica gel with 30% ethyl acetate in hexane using medium pressure liquid chromatography (MPLC). The title compound (Rf 0.21) was isolated as a gum (0.906 g). NMR (CHCl3, 300 MHz) δ 7.2-7.4 (20H, m), 4.70 (1H, d, J=8 Hz), 3.63 (1H, br s), 3.50 (1H, d, J=13 Hz), 3.36 (1H, d, J=13 Hz), 3.2-3.35 (5H, m), 2.75 (1H, m), 2.0-2.6 (10H, m), 1.75 (2H, m), 1.42 (9H, s). A diastereomeric minor product (Rf 0.14) was also isolated (0.065 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:31][Si](C)(C)C)=[CH:28][CH2:29][CH3:30]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH2:29][CH3:30])[C:27]([O:26][CH3:25])=[O:31])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC=C(OC)O[Si](C)(C)C
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (250 mg, 0.79 mmol) and (1-methoxybut-1-enyloxy)trimethylsilane (32 mmol) which was prepared using General Silyl Ketene Acetal Method A in 10 mL of dry DCM was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 by MPLC using a EtOAc/hexane gradient to give 200 mg (63% yield) of methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoate. MS found: (M+H)+=403.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O1CCNC1=O>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[CH2:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1NCCO1
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (17.0 g, 72.8 mmol) in tetrahydrofuran (200 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (80 mL, 79.4 mmol) and stirred for 1 hour. A solution of 1-(benzyloxy)-4-(bromomethyl)benzene (746) (20.0 g, 72.2 mmol) in tetrahydrofuran (50 mL) was added slowly to the oxazolidinone solution at −78° C. and allowed to warm to room temperature overnight. The solvent was removed in vacuo and the residue was dissolved with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford (R)-4-benzyl-3-((R)-3-(4-(benzyloxy)phenyl)-2-methylpropanoyl)oxazolidin-2-one (747).