Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[CH:17]2[Si:22]([CH:25]1[C:33]2[C:28](=[C:29](Br)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35])([CH3:24])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[CH:17]2[Si:22]([CH:25]1[C:33]2[C:28](=[C:29]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:11])[CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3c(C)cc(C)cc3C)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3c(C)cc(C)cc3C)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF. 13.0 ml of 1.0 M mesitylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.60 g (94%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18].[F-].[K+].C1OCCOCCOCCOCCOCCOC1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)CCN
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CCNc1c(F)cccc1[N+](=O)[O-]

Procedure:
To a solution of 1,2-difluoro-3-nitrobenzene from Example B1 (500 mg, 3.1 mmol) in acetonitrile (25 ml) were added β-alanine methyl ester hydrochloride (440 mg, 3.1 mmol), potassium fluoride (310 mg, 5.3 mmol), 18-crown-6 (84 mg, 0.3 mmol) and diisopropylethylamine (1.2 ml, 7 mmol). The mixture was stirred at reflux for 2 h, cooled and evaporated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 25:75); yield 650 mg, 86%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with N-methylaniline (729 mg, 6.8 mmol) using method A to give 4-(N-methyl-N-phenylsulfamoyl)benzoic acid as an off-white solid. Yield: 374 mg (57%). 1H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.38-7.28 (m, 3H), 7.13-7.08 (m, 2H), 3.17 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH2:14][OH:15]>C(O)C>[Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2cnccc12
Solvent: CCO
Product: ON=Cc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-bromo-5-isoquinolinecarboxaldehyde (i.e. a product from Step A) (75 mg, 0.3 mmol) in ethanol (7 mL) was added an aqueous solution of hydroxylamine (0.5 mL, 50% in water). After stirring at room temperature, overnight, the reaction mixture was concentrated under reduced pressure to provide the title compound as a yellow solid (70 mg).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH2:6]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C1=CCC=C1
Reactant: [Li]CCCC
Agent: [Zr+4]
Agent: [Cl-]
Product: CCCCC1=CC=CC1
Temperature: 0 °C

Procedure:
n-Butylcyclopentadiene was prepared analogously to Example 1 and freed or inorganic salts and excess cyclopentadiene. The solution so obtained was cooled to 0° C. and subsequently admixed dropwise with 9.7 g of n-butyllithium (90% strength in hexane; 136 mmol). The mixture was allowed to react for a further 30 minutes while stirring. 15.8 g of ZrCl4 (68 mmol) was added at 0°-10° C. and the mixture was stirred for 2 hours at room temperature.
Reaction SMILES: CN(C)C(N(C)C)=N.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]12[CH2:24][NH:23][CH2:22][CH:21]1[CH2:20][S:19][C:18]([NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:17]2.[F:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1.C(OCC)(=O)C>CS(C)=O.O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]12[CH2:24][N:23]([C:38]3[N:39]=[CH:40][C:35]([F:34])=[CH:36][N:37]=3)[CH2:22][CH:21]1[CH2:20][S:19][C:18]([NH:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:17]2
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=NC2(c3ccccc3F)CNCC2CS1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
N,N,N′,N′-tetramethylguanidine (0.44 mL, 3.5 mmol) is added to a solution of racemic N-[7a-(2-fluorophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.0 g, 2.9 mmol) and 5-fluoro-2-chloropyrimidine (0.46 g, 3.5 mmol) in dimethylsulfoxide (10 mL). The reaction is stirred at 100° C. for 2 hours, and cooled to room temperature. To the crude reaction is added ethyl acetate (7.5 ml) and water (2.5 ml), the mixture is passed through diatomaceous earth (10 g), and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with a gradient of 40% to 60% ethyl acetate in hexanes to give the title compound (560 mg, 43%). ES/MS (m/e): 452 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:24])[C:16]2[CH:15]=[C:14]3[C:17]4[C:22]([NH:23][C:13]3=[CH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4.Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]=1>ClCCl>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=[C:26]([N:23]3[C:13]4[C:14](=[CH:15][C:16]5[C:4]([CH3:24])([CH3:3])[C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=6[C:11]=5[CH:12]=4)[C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC1(C)c2ccccc2-c2cc3[nH]c4ccccc4c3cc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g (37.5 mmol) of NaH (60% in oil) are initially introduced in 150 ml of dichloromethane. A solution of 8 g (28 mmol) of 12,12-dimethyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene in dichloromethane is added dropwise at room temperature. After 1 h, 8.5 g (31 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine are added dropwise, and the mixture is stirred at RT for 8 h. The solid which has precipitated out is recrystallised from toluene. The crystals which have deposited are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 11.6 g; 80% of theory; purity: 99.9% according to HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1 of Example 97, single enantiomer) and isobutyryl chloride (31 mg, 0.29 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:15][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc2[nH]c(S)nc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]c(SC)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.6 %

Procedure:
To a solution of methyl 2-sulfanyl-1H-benzimidazole-4-carboxylate (prepared as described in WO2003/106430) (1.0 g) in DMF (15 mL), were added potassium carbonate (700 mg) and methyl iodide (0.32 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (860 mg) as white powder.
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:6][C:5]([CH3:12])([C:7]([O:9]CC)=[O:8])[CH2:4]1.[OH-].[Na+]>C1COCC1.O>[F:1][CH:2]([F:13])[CH:3]1[CH2:4][C:5]([CH3:12])([C:7]([OH:9])=[O:8])[CH2:6]1
Reactant: CCOC(=O)C1(C)CC(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC(C(F)F)C1

Procedure:
A solution of Intermediate 258D (0.07 g, 0.364 mmol) and NaOH (0.036 g, 0.910 mmol) in THF (2 mL) and water (1 mL) was stirred at RT for 16 h. The volatiles were evaporated under reduced pressure, the pH was adjusted to =3 with a 1.0N aq. solution of HCl, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 258E (0.05 g, 84%, a mixture of cis and trans isomers) as a yellow liquid. The crude product was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.20-12.36 (m, 1H), 5.86-6.24 (m, 1H), 2.57-2.86 (m, 1H), 2.27-2.46 (m, 2H), 1.77-1.93 (m, 2H), 1.36 (s, 1H), 1.27 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:38][CH2:39][C:40](=[O:42])[CH3:41]>C1COCC1>[O:42]=[C:40]([CH3:41])[CH2:39][CH2:38][O:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=c1oc2ccccc2cc1O
Reactant: CC(=O)CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CCOc1cc2ccccc2oc1=O
Temperature: 25 °C

Procedure:
3-Hydroxy-chromen-2-one (16.2 g, 100 mmol) is dissolved into 100 mL of anhydrous THF in a three neck flask equipped with a condenser, stir bar, and argon inlet. To the mixture is added 27.6 g (200 mmol) of anhydrous potassium carbonate and 2.0 g of 18-crown-6. 4-Chloro-2-butanone (15.9 g, 150 mmol) is added and the system is refluxed for 16 hours, cooled to room temperature, filtered, and the organic solvents are removed by rotary evaporation. The solid organic residue is purified by column chromatography using 3:1 ethyl acetate:hexanes to yield 3-(3-oxo-butoxy)-chromen-2-one.
Reaction SMILES: [CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].CCN(C(C)C)C(C)C.CS(O[CH2:40][CH2:41][CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=2[N:45]=[N:44]1)(=O)=O>CN(C=O)C>[CH:1]1([C@@:6]([OH:23])([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]([CH2:40][CH2:41][CH2:42][N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH:52]=[O:53])=[CH:51][C:46]=4[N:45]=[N:44]3)[CH3:17])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCCCn1nnc2cc(C=O)ccc21
Reactant: CN[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCCn1nnc2cc(C=O)ccc21)[C@H]1CC[C@H](OC(=O)[C@](O)(c2cccs2)C2CCCC2)CC1
Temperature: 75 °C
Reaction time: 7 h

Procedure:
To a solution of trans-4-(methylamino)cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate (Intermediate 172 from WO2011/141180A1, 318 mg, 0.93 mmol) in DMF (3 mL) was added sodium iodide (355 mg, 2.37 mmol) and DIEA (0.25 mL, 1.44 mmol). To this suspension a solution of 3-(5-formyl-1H-1,2,3-benzotriazol-1-yl)propyl methanesulfonate (Intermediate 99, 380 mg, 1.17 mmol) in DMF (2 mL) was added and the mixture was stirred at 75° C. for 7 hours. The reaction mixture was evaporated to dryness, the solid residue was re-suspended in CHCl3 (30 mL) and the suspension was filtered through Celite®. The solvent was removed under reduced pressure and the resulting yellow solid was purified by column chromatography over silica gel eluting with a mixture of CH2Cl2/EtOH (gradient from 0 to 100% of EtOH) to provide the title compound as a yellow solid (473 mg (70% purity by HPLC), 68% yield).
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[C:13]=1[CH:14]=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1O
Agent: O=S(=O)(O)c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=O)c1O
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde benzenesulfonate (200 g, 0.685 mole) was added to 90% nitric acid (400 mL) with the temperature maintained at 0°±2° over a period of onehalf to one hour. The reaction mixture was stirred an additional 0.5 hour and poured over ice (2.5 L) with stirring. After standing several hours, the solid was collected by filtration and washed with water (500 mL). The solid was then suspended in acetone (1.25 L) and the mixture was heated to reflux for 0.5 hour, concentrated to 500 mL and cooled to 15° C. The resultant solid was collected by filtration and washed with cold acetone (125 mL) to provide the title compound, 138.5 g (60%), mp 151-155° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)c1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), methyl 5-hydroxy-3-pyridinecarboxylate (2.0 g), and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.58 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography to give crystals (2.41 g, 0.43%) of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-139° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([F:16])([F:15])[CH2:8][CH2:9][C:10](OCC)=[O:11])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C.C(OCC)(=O)C>[F:15][C:7]([F:16])([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCC(F)(F)CCC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCCCC(F)(F)CCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67983.8 %

Procedure:
To a solution of 4,4-difluoro-heptanedioic acid diethyl ester (1.3 g, 5.65 mmol) in diethyl ether (35 ml) at 0° C. under N2 was slowly added solid LAH (638 mg, 11.80 mmol). The resulting mixture was allowed to stir for 30 mins at room temperature and then heated to reflux for two hours. Upon cooling, water (0.5 ml) was added, followed by 15% NaOH (0.5 ml) and water (1.5 ml). The resulting mixture was stirred for another two hours at room temperature and then diluted with ethyl acetate (500 ml). The organic solution was dried over Na2SO4 without aqueous work-up. Evaporation of the solvent gave the title compound (646 g, 68%) as pure colorless oil. 1H NMR (CDCl3) δ 1.71–1.80 (m, 4H), 1.87–2.03 (m, 4H), 3.69 (t, 4H, J=60 Hz); 19F NMR (CDCl3) δ −22.64–22.28(m); 13C NMR (CDCl3) δ 25.81, 25.87, 25.92, 32.99, 33.33, 33.67, 122.38, 125.56, 128.74.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]5[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (104 mg, 82%), MS (ISP) m/z=511.4 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-methanesulfonyl-benzoic acid.
Reaction SMILES: [CH2:1]=O.[Br:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][NH2:14])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1>C(O)=O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[C:5]=1[CH2:1][NH:14][CH2:13][CH2:12]2
Reactant: C=O
Reactant: COc1cc(Br)cc(CCN)c1
Solvent: O=CO
Product: COc1cc(Br)c2c(c1)CCNC2
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Paraformaldehyde (660 mg; WAKO) was added to a formic acid (50 mL) solution of Intermediate 4 (4.33 g) at 50° C. and the resulting mixture was stirred as it was for 13 hours and 30 minutes. The solvent was evaporated under reduced pressure followed by the addition of dichloromethane (100 mL) and 1 N aqueous sodium hydroxide solution (100 mL) to extract the reaction mixture, and the aqueous layer was further extracted with dichloromethane. The organic layer was combined and dried and then the solvent was evaporated under reduced pressure to give the title compound (4.49 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[CH2:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30])[CH3:26]>>[CH2:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:30])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: CCc1cccc(C)c1C(=O)O
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-ethyl-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-ethyl-6-methylbenzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 127-133° C. ES-HRMS m/e calcd for C26H29N3O5 (M+Na) 494.1498, found 494.1501.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][C:68]=2[CH3:74])[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:74][C:68]1[CH:69]=[C:70]([CH3:73])[CH:71]=[CH:72][C:67]=1[C:57]1[C:56]([CH3:75])=[C:55]([NH:47][C:46]2[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[N:42][CH:43]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:45]=2)[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c(C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.022 g, 0.045 mmol), 2,5-dimorpholinopyridin-3-amine (0.090 g, 0.34 mmol), 4-chloro-2-(2,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline (0.090 g, 0.28 mmol), Pd2dba3 (10.4 mg, 0.011 mmol) and sodium tert-butoxide (0.068 g, 0.71 mmol) in toluene (2.8 mL) at 120° C. for 3.3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(2,4-dimethylphenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.46 (1H, s), 8.70 (1H, d, J=4.8 Hz), 8.02 (1H, td, J=7.8, 1.8 Hz), 7.98 (1H, d, J=5.7 Hz), 7.89 (1H, dt, J=7.8, 1.2 Hz), 7.67 (1H, br. dd, J=2.2, 1.8 Hz), 7.65 (2H, dt, J=8.4, 1.6 Hz), 7.52 (1H, ddd, J=7.6, 4.9, 1.4 Hz), 7.47 (1H, ddd, J=12.1, 9.2, 2.5 Hz), 6.10 (1H, br. s), 3.48 (4H, br s), 3.40-3.30 (8H, m), 2.27 (3H, s). Mass Spectrum (ESI) m/e=546.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:4]([C:3]1[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: O=C(O)c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 95 °C

Procedure:
To 2-chloronicotinonitrile (900 mg, 6.50 mmol), 2-fluoro-5-hydroxybenzoic acid (1.0 g, 6.4 mmol) and cesium carbonate (4.2 g, 13 mmol) was added DMSO (7 mL). The mixture was heated to 95° C. for 18 hours in a sealed tube. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 6 N HCl (pH˜2) and then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 5-(3-cyanopyridin-2-yloxy)-2-fluorobenzoic acid. MS m/z 257=[M+H]+. Calc'd for C13H7FN2O3: 258.21.