Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].Cl[Si](CC)(CC)CC.[CH3:11][O:12][C:13](=[O:32])[C@H:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:15]1[CH2:20][CH:19](O)[C:18]2[S:22][CH:23]=[CH:24][C:17]=2[CH2:16]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:11][O:12][C:13]([C@@H:14]([N:15]1[CH2:16][C:17]2[CH:24]=[CH:23][S:22][C:18]=2[CH2:19][CH2:20]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])=[O:32]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: CC[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of sodium iodide in dichloromethane is added chlorotriethylsilane. The mixture is stirred at room temperature under nitrogen for 90 min. A solution of (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (9) (8.2 g, 24.3 mmol) in dichloromethane is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 3 hours. Water is then added to the mixture at 0–5° C. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oily product (6.69 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: Br[C:2]1[C:3]([Cl:12])=[N:4][C:5]([O:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1>[Cl:12][C:3]1[C:2]([C:19]([OH:20])([CH3:21])[CH3:18])=[C:7]([O:8][CH3:9])[N:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: COc1nc(Cl)c(Br)c(OC)n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(Cl)c(C(C)(C)O)c(OC)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
To a solution of 5-Bromo-4-chloro-2,6-dimethoxy-pyrimidine (0.546 g, 2.16 mmol) in THF (22 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) over 2 min. Reaction mixture was stirred from 45 min at −78° C., then acetone (0.31 mL, 4.32 mmol) was added. Reaction mixture was stirred for 1 h at −78° C., then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with saturated ammonium chloride solution, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 10 to 30% ethyl acetate/hexane) to give a colorless oil (0.275 g, 55%). 1H NMR (300 MHz, CDCl3): δ 3.97 (br s, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 1.54 (s, 6H). Mass spectrum: 233.0, 235.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[C:24]#[N:25])([O-])=O.[Sn](Cl)[Cl:27]>C(O)C.Cl>[ClH:27].[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:5]2[NH:14][C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([NH2:25])=[N:1][C:4]=2[CH:9]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(C(F)(F)F)ccc2Nc2sc3ccccc3c21
Yield: 97.5 %

Procedure:
Combine 2-(2-nitro-4-trifluoromethyl-phenylamino)-benzo[b]thiophene-3-carbonitrile (5.14 g, 14.1 mmol) and tin(II) chloride (8.05 g, 42.4 mmol) in absolute ethanol and 5N HCl (60 mL each) and reflux the suspension for 1.5 hours. Cool the reaction to ambient temperature. Collect the reaction solid by suction filtration, wash it with cold ethanol, and dry it at 40° C. under reduced pressure to give the title compound (5.083 g). Isolate a second crop of material from the initial filtrate and dry at 40° C. under reduced pressure to give the title compound (0.482 g). Total solid: 5.20 g (94.6%). Mass spectrum (APCI+, m/e): 334 (M+1-HCl); NMR (1H, 300 MHz, DMSO-d6), δ (ppm): 11.71 (s, 1H), 10.32 (s, 1H), 9.32-9.10 (m, 2H), 7.94-7.85 (m, 1H), 7.74-7.65 (m, 1H), 7.60-7.51 (m, 1H), 7.49-7.40 (m, 1H), 7.39-7.27 (m, 2H), 7.23-7.14 (m, 1H).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[OH:15])(=[O:4])[CH3:3].[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C.C(Cl)(Cl)Cl.O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:2](=[O:4])[CH:3]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:15][C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Reaction time: 0.25 h

Procedure:
A solution of sodium metal, (18.4 g, 0.8 gatom), in dry ethanol (1200 ml), was treated with N-(4-acetyl-3-hydroxyphenyl)acetamide (30.88 g, 0.16 mole). This mixture was stirred for 15 mins then diethyl oxalate (58.4 g, 54.3 ml, 0.4 mole), was added dropwise over 30 mins. The resulting mixture was heated and stirred at 60° C. for 2 hrs, allowed to cool and poured into a mixture of chloroform (600 ml), conc HCl (85 ml), and water (2000 ml). The organic layer was isolated and combined with a chloroform wash of the aqueous layer. The combined chloroform extracts were washed well with water then evaporated to dryness. The residue was taken into ethanol (400 ml), and conc.HCl (10 ml), was also added. The solution was heated at reflux for 30 minutes then evaporated to dryness. The residue was treated with ether and ethanol was added dropwise until the residue began to solidify. Insoluble material was filtered off, washed again with ether and the required sub-title product was recovered as a brown solid (20.5 g), (55%), mp 192°-194°. NMR and mass spectra confirmed the structure.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[OH-].[K+].[C:28](=[S:30])=S>CO>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:20])([CH3:19])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:28](=[S:30])[NH:25][N:24]=2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc(-c2n[nH]c(=S)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-pyrimidine carboxylic acid hydrazide (0.9 g, 2.5 mmoles), KOH (0.16 g, 2.8 mmoles), and carbon disulfide (0.44 g, 5.8 mmoles) are dissolved in 20 mL of MeOH. The reaction mixture is warmed to reflux under argon for 24 hours. It is cooled to room temperature, quenched with 150 mL of 10% HOAc/H2O, and extracted with ether (3×100 mL). The ether extract is washed with brine (3×100 mL) and evaporated. The oil remaining is taken up in 20 mL of TFA and stirred at room temperature for 30 minutes. The TFA is evaporated on the rotovap, and the oil is partitioned between 100 mL of ether and 100 mL of H2O. The pH of the water layer is adjusted to 5 by the addition of saturated sodium bicarbonate. The layers are separated and the organic layer is washed with 50 mL of brine. Drying over MgSO4 and evaporation of solvent gives a yellow oil. Flash chromatography in 50% Et2O/hexane followed by two recrystallizations from Et2O/hexane gives 0.16 g (20%) of 5-[ 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-1,3,4-oxadiazole-2 (3H)-thione, 234°-236° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]I
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Solvent: C1CCOC1
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgI solution (3 M in THF, 4.48 mL, 13.45 mmol) and the resulting solution was stirred at reflux for 5 h. Then the reaction mixture was cooled to rt, quenched with water, washed with NH4Cl solution and extracted by DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (95%) of the title compound which was used to next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])[C:9]([NH2:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)Cc1ccc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 85 °C
Yield: 39 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenyl)acetamide (29.7 mmol) and N-bromosuccinimide (37.2 mmol) in anhydrous carbon tetrachloride (85 ml) was added 2,2′-azobis(2-methylpropionitrile) (1.487 mmol). The reaction mixture was heated at 85° C. for 4 days. The resulting suspension was concentrated in vacuo and the residue was taken into brine and then extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and decolorizing charcoal, filtered through a short pad of celite, and evaporated to a crude residue. Purification of the residue by flash chromatography (30% ethyl acetate in hexanes) afforded the title product (3.60 g, 38% yield) as a cream-colored solid. MS(ES)+m/e 310.1, 312.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.79 (s, 1 H) 7.48 (dd, J=8.59, 1.77 Hz, 1 H) 7.59 (br. s., 1 H) 7.61 (dd, J=9.85, 2.02 Hz, 1 H) 7.70 (t, J=8.21 Hz, 1 H) 7.91 (br. s., 1 H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[O:21][N:20]=1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][S:14][C:9]3[C:10]([O:12][CH3:13])=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]([CH3:15])[CH:8]=3)[CH:23]=2)=[CH:29][CH:28]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cc(-c2ccc(Cl)cc2)on1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1D and 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole. MS m/z 434 (M+1).
Reaction SMILES: C(OC(=O)[C:5]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([I:23])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:24]#[N:25])([CH2:11][CH3:12])C(OCC)=O)C.[Cl-].[Li+].O.CS(C)=O>CCCCCC.C(OCC)(=O)C>[I:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([C:24]#[N:25])=[C:13]2[CH2:5][CH2:11][CH3:12]
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCCc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 2-(3-cyano-6-iodo-quinolin-4-yl)-2-ethyl-malonic acid diethyl ester (example 71a, 250 mg, 0.54 mmol), lithium chloride (45 mg, 0.72 mmol), water (10 uL, 0.54 mmol), and dimethylsulfoxide (10 uL) was heated at 180 degrees for 1 hour. After cooling to the room temperature, the reaction was quenched with water, followed by addition of ethyl acetate. The insoluble material was removed by filtration through a plug of celit with ethyl acetate. The water layer was extracted with ethyl acetate two more times. The organic layers were combined, washed with brain, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product as dark viscous oil. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 10-20% ethyl acetate in hexane in 30 min) afforded 6-iodo-4-propyl-quinoline-3-carbonitrile (40 mg, 23%) as a solid. LC-MS m/e 323 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3- phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.6 mg, 37.9% yield) as a thick oil. 1H NMR (400 MHz, CDCl3) δ 7.38-7.14 (m, 8H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.72-6.46 (m, 4H), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37-1.72 (m, 8H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([OH:33])[CH:26]=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:34])=[CH:26][C:27]=1[O:33][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Product: COC(=O)c1ccc(OC)c(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1

Procedure:
The title compound was prepared from (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) and methyl-3-hydroxy-4-methoxybenzoate using the method of Example 264 Step 3; MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: Br[CH2:2][C:3](=[O:19])[C:4]([OH:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[OH:18][C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:3](=[O:19])[CH2:2][N:30]1[CH2:31][CH2:32][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(CBr)C(O)(CN1CCCCC1)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCN(Cc2ccccc2)CC1)C(O)(CN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 63 g (5 mmole) of 4-bromo-2-hydroxy-2-phenyl-1-piperidino-3-butanone in 35 mL of ether is added 1.76 g (5 mmole) of 4-benzylpiperazine. The solution is stirred at room temperature for 18 hours and then washed twice with brine dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Purification by flash column chromatography gives 2-hydroxy-2-phenyl-1-piperidino-4-(4-benzyl-1-piperazinyl)-3-butanone. This was converted into its hydrochloride salt in the usual manner.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)=[O:3].Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:8]([CH:12]=1)[C:9]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:11])=[O:3]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: NC(=O)c1ccc(Oc2cccc(F)c2)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C(N)=O)ccc2Oc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-(Aminocarbonyl)-2-(3-fluorophenoxy)benzoic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.60 (1H, d, J=2.4 Hz), 8.05 (1H, dd, J=8.6, 2.4 Hz), 7.91 (2H, d, J=8.4 Hz), 7.83 (1H, d, J=7.2 Hz), 7.42–7.27 (3H, m), 7.00–6.77 (5H, m), 6.12 (1H, br.s), 5.32–5.22 (1H, m), 3.89 (3H, s), 1.51 (2H, d, J=7.0 Hz); MS (ESI) m/z 437 (M+H)+, 435 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:22]#[N:23].C(N(CC)CC)C>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:18][C:19]2[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][C:26]=2[NH:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NC2CCCCC2)c(N)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC2CCCCC2)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of the acid chloride of 4-benzyloxybenzoic acid (2.56 g, 10.4 mmol) in dichloromethane (30 mL) and dimethylformamide (5 mL) was added dropwise to a solution of compound 4 (2.23 g, 10.4 mmol) and triethylamine (2.4 mL, 17.2 mmol) in dichloromethane (15 mL). After 1.5 h, 4-dimethylaminopyridine (0.12 g) was added. The reaction was stirred at rt for 18 h and then heated to 45° C. for 4 h. The reaction was cooled to rt and then extracted with 1 N KHSO4 (1×) and brine (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 10-20% ethyl acetate/hexanes (v/v)) to afford compound 11 as a slightly purple solid (2.08 g, 47%). ESI-MS m/e 426.3 (M+1).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:16][C:17]1[C:22]([CH:29]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[OH:30])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=Cc1cccnc1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2,2,6,6 Tetramethyl piperidine (1.97 ml, 11.6 mmol) is added dropwise to a solution o of n-Butyl lithium (6.87 ml, 11.0 mmol of 1.6 M solution in THF) in THF (40 ml) at −78° C., and the resulting solution stirred at this temperature for 5 minutes. The reaction mixture is allowed to warm to 0° C. and the reaction stirred at this temperature for 35 minutes. The reaction is cooled to −78° C., and 2-chloropyrazine (0.78 ml, 8.73 mmol) is added dropwise to form a red solution, which is stirred at −78° C. for 40 minutes. Pyridine-3-carbaldehyde (0.93 ml, 9.95 mmol) is added dropwise and stirred at −78° C. for 1 hour and 40 minutes. The reaction is quenched using 5M HCl (5 ml) at −78° C. and the reaction then allowed to warm slowly to room temperature. The pH is adjusted to 7 by the addition of sat. aq. NaHCO3 solution, and the product extracted into ethyl acetate (2×200 ml), dried (MgSO4) and the solvent removed in vacuo to afford a black oil which is purified using flash chromatography (SiO2, iso-hexane/EtOAc) to afford (3-chloro-pyrazin-2-yl)-pyridin-3-yl-methanol as a pale brown solid [M+H]+ 222.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1>>[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)C
Yield: 72.9 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine (193 mg, 0.8 mmol) were reacted to give the title compound as a pale solid (272 mg, 74%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.59 (s, 2H), 6.81 (d, 1H), 6.87 (d, 1H), 6.96 (m, 2H), 7.25 (m, 1H), 7.34 (d, 1H), 7.47 (d, 1H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.07 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum 485.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:37][C:38]#[C:39][Si](C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.ClCCl.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C@H:11]([CH2:39][C:38]#[CH:37])[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate (633 mg, 1.76 mmol) was dissolved in tetrahydrofuran (6 ml) and at −78° C., lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 3.87 ml) were added dropwise. After 30 min, 3-bromo-1-(trimethylsilyl)-1-propyne (370 mg, 1.94 mmol) in tetrahydrofuran (2 ml) was added dropwise and the mixture was stirred at −78° C. for 3 h. The reaction was than warmed to 0° C. and 10 ml of 1 N hydrochloric acid were added. The mixture was extracted with dichloromethane, dried and concentrated in vacuo. The residue was purified by silica gel chromatography to give the intermediate TMS-protected alkyne. The intermediate was dissolved in 30 ml dichloromethane/methanol (1:1). Potassium carbonate (1 g) was added and the mixture was stirred for 1 h. Water (20 ml) was added and the mixture was extracted with dichloromethane, dried and concentrated in vacuo. The product (416 mg, 59%) was used in the following reaction without further purification.