Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[O:18]1[CH2:19][CH:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3COC3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(C3COC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.2 %

Procedure:
A 250-mL round-bottomed flask was purged with nitrogen and charged with 117d (1.5 g, 5.7 mmol), 10% palladium on carbon (50% wet, 750 mg), and ethanol (60 mL). The flask was evacuated, charged with hydrogen gas, and stirred at room temperature for 15 h. The hydrogen was then evacuated and nitrogen charged into the flask. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 117e (1.2 g, 90%), which was used in the next step without further purification. MS: [M+H]+ 234
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:6][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 100 °C
Yield: 90.4 %

Procedure:
To an ambient temperature solution of 6-chloro-nicotinic acid methyl ester (12.4 g, 72 mmol) and 4-(trifluoromethyl)phenylboronic acid (15 g, 79 mmol) in dioxane (270 mL) is added CsF (38.3 g, 252 mmol) and the reaction mixture is degassed with nitrogen. PdCl2(dppf) (1.5 g) is added and the reaction mixture is heated to 100° C. over weekend. The reaction mixture was diluted with ethyl acetate, filtered through celite. The filtrate is concentrated. Purification of the crude product by column on silica gel (hexanes/ethyl acetate) gives 6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (18.3 g, 82.3% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:16]=1[CH2:17]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[C:15]([F:14])=[CH:22][CH:21]=[CH:20][C:19]=1[F:23])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: Fc1cccc(F)c1CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1c(F)cccc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2,6-difluorobenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].CO.C=O.[BH3-][C:42]#N.[Na+]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:42])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole and MeOH was added formaldehyde, followed by AcOH. The reaction was stirred for 20 min, NaCNBH3 was added to the reaction mixture and was continued to stir for another 30 min. After a routine aqueous work up, the crude product was purified by prep HPLC to give 2-[1-(2-chlorophenyl)-1-methylethyl]-4-(1-methylpyrrolidin-2-yl)-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazole: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (s, 1H), 1.9 (s, 3H), 2.2-2.5 (m, 4H), 2.8 (s, 3H), 3.2 (s, 3H), 3.6 (br, 1H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 5H), 7.4 (s, 1H), 7.7 (m, 3H), 8.0 (m, 2H), 8.2 (m, 1H); LC/MS M+H 534 (observed).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9](OCC)=[O:10].[CH3:14][CH:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]([O:21][CH:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:10]
Reactant: CCOC(=O)COc1ccccn1
Reactant: CCCCCC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(C)OC(=O)COc1ccccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
5.0 g (28 mmol) of ethyl 2-pyridyloxyacetate were suspended in 100 ml of 2-heptanol, 1 ml of titanium tetraisopropoxide were added, and the mixture was stirred for 4 hours at 120° C. The excess 2-heptanol was subsequently distilled off under an oil pump vacuum, and the residue was purified by column chromatography. 6.2 g (90% of theory) of (1-methyl)hexyl 2-pyridyloxyacetate were obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[OH:32]>C(OCCO)C>[OH:32][C:31]1[CH:30]=[C:29]([CH3:33])[CH:28]=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1ccc(N)c(O)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)cc3O)c2cc1OC
Yield: 85.7 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 6-amino-m-cresol to give 287.5 mg (85.8%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 335.9.
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([OH:14])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:21]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([NH2:21])=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1OCCCS2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c1OCCCS2
Reaction time: 48 h
Yield: 64 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid (16.5g, 78.4 mmol) in 100 mL DMF was added in succession solid HOBT (21.3g, 157.3 mmol), solid EDC hydrochloride (30.1 g, 157.0 mmol), and 25% aqueous ammonia (18 mL, 128.4 mmol). After stirring for 48 h, the reaction mixture was diluted with 200 mL ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, saturated NH4Cl, and brine. Drying over Na2SO4 and concentration yielded the amide as a tan solid (10.5 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCCCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-pentylaniline to yield 2-[(4-pentylphenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccccc2)c1I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.9 %

Procedure:
Large Scale: A mixture of ethyl 5-phenylisoxazole-3-carboxylate (3.05 g, 14.0 mmol) and N-iodosuccinimide (3.79 g, 16.9 mmol) in trifluoroacetic acid (78 mL) was stirred at room temperature for 3.5 h. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (150 mL), washed with a 3% aqueous solution of sodium bisulfite (2×150 mL), washed with brine (150 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 4-iodo-5-phenylisoxazole-3-carboxylate (4.69 g, 13.7 mmol, 97% yield) as a light yellow oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([OH:30])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3C(=CC=C4C[C@@H](O)C[C@H](O)[C@@]43C)[C@@H]1CC[C@@H]2CO
Yield: 96.2 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene (1.0 g), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (11 ml), followed by reflux for 6 hours. After adding ethyl acetate, the reaction mixture was washed with saturated brine, a saturated aqueous sodium bicarbonate solution (twice) and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the titled compound (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Cl:23])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To the solution of (4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methanol (3 g, 9.91 mmol) in DCM (90 mL), was added thionyl chloride (7.5 mL, 103 mmol) dropwise. The mixture was stirred at room temperature for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4. Concentration in vacuo afforded the title compound (2.8 g, 88% yield) as light brown oil. LCMS: rt=4.14 min
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:13][C:14]#[N:15])([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=C1CC(OCc2ccccc2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(OCc5ccccc5)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
To a mixture of [3-(benzyloxy)cyclobutylidene]acetonitrile (0.1 g, 0.0005 mol) and 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.0003 mol) under nitrogen. The mixture was heated at 50° C. overnight, then concentrated under reduced pressure. The residue was purified with combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product as cis- and trans-isomer mixture. LCMS calculated for C28H35N6O2Si(M+H)+: 515.3; Found: 515.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][CH:72]=1)([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:72]=[CH:73][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:75][CH:76]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 4-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 55 mg.
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[N:7]=[C:6]([C:13]([O:15]C)=[O:14])[C:5]=1[Cl:17]>O.O1CCCC1>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([CH2:11][CH3:12])[N:7]=[C:6]([C:13]([OH:15])=[O:14])[C:5]=1[Cl:17]
Reactant: CCc1nc(C(=O)OC)c(Cl)c(N)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of lithium hydroxide (0.49 g, 11.73 mmol) in water (25 mL) was added to a solution of methyl 4-amino-3-chloro-6-ethyl-5-fluoropyridine-2-carboxylate (1.36 g, 5.86 mmol) in tetrahydrofuran (25 mL). The mixture was vigorously stirred at room temperature overnight and was then concentrated to half volume. After adding water the reaction mixture was washed once with ethyl acetate to remove unreacted starting material. The aqueous layer was then acidified to pH<3 with 1N HCl, concentrated and the residue partitioned between tetrahydrofuran and brine. The aqueous layer was discarded and the organic layer concentrated and dried under vacuum to provide 4-amino-3-chloro-6-ethyl-5-fluoropyridine-2-carboxylic acid (1.01 g, 4.60 mmol) as a white solid, mp 144-145° C.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH2:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH2:14][CH3:15]
Reactant: CCc1cc(C(C)=O)cnc1OCC(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: CCc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (240 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-ethylpyridin-3-yl)ethanone (220 mg, 0.94 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 56.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.23 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), triethyl amine (10 g) and chloroform (250 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (7.6 g) was obtained as a light pink solid, m.p. 152°-154° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.36; H, 4.79; N, 10.35. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:10][Si:11]([Cl:14])(Cl)Cl.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:10][Si:11]([Cl:14])([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](Cl)(Cl)O[Si](C)(C)C
Yield: 19.8 %

Procedure:
About 1.9 ml of a 25% solution of phosphonitrile chloride in methylene chloride are added at room temperature with stirring to a mixture containing 486 g (3.0 mol) of hexamethyldisiloxane and 170 g (1.0 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 8 hours, the catalyst is deactivated by adding 2.2 ml of tri-n-butylamine. Distillation of the reaction mixture at 18° to 34° C. and at 2 mbar gives 55 g of 3,3-dichlorohexamethyltrisiloxane, but no 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane. Likewise the desired 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane is neither found in the distillation residue (12 g) nor in the cold trap (583 g of a mixture of trimethylchlorosilane and 1,1,1-trichloro-3,3,3-trimethyldisiloxane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1([Si:16]2([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=CC=CC=1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Si@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:27])=[CH:29][CH:30]=2)[CH2:20][CH2:21]1
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: COCCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(Cl)c(Cl)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-dichlorophenol and 4-(4-phenyl-4-(5-methoxypentyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [CH2:1]([C:4]1[N:13]=[C:12]2[C:7]([C:8](O)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[CH:9]=[CH:10][N:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[N:13]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1ccc2c(O)ccnc2n1
Product: CCCc1ccc2c(Cl)ccnc2n1
Yield: 86 %

Procedure:
The product from Example 2f (145 mg, 0.76 mmol) was reacted with POCl3 4 mL following the procedure from Example 1d giving the title compound as a solid (135 mg, 86%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]3[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:14]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]3[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:14]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)OCCO3)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2ccc3c(c2)OCCO3)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 4-((E)-2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)vinyl)-2-(4-fluoroanilino)benzoate was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give 4-((E)-2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)vinyl)-2-(4-fluoroanilino)benzoic acid 17 mg of pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl[C:34]1[O:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1>>[O:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[N:6]([CH2:5][C:4]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:3]=1[C:2]([F:32])([F:1])[F:31])[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:19])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Clc1nc2ccccc2o1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
Similarly prepared from methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorobenzoxazole.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7]Br.[C-:10]#[N:11].[K+]>CCO.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7][C:10]#[N:11]
Reactant: [C-]#N
Reactant: BrCc1c(Br)csc1Br
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Br)csc1Br
Yield: 85.4 %

Procedure:
To a solution of 2,4-dibromo-3-(bromomethyl)thiophene (1.00 g, 3.00 mmol) in EtOH (10 mL) was added a solution of potassium cyanide (0.29 g, 4.5 mmol) in H2O (0.5 mL). The mixture was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc was dried (MgSO4) and the solvent removed. The residue was recrystalized from EtOH to yield (2,4-dibromothien-3-yl)acetonitrile (0.72 g, 86%). mp 75.5-77° C.; 1H NMR (500 MHz, DMSO-d6) δ: 3.94 (s, 2H), 7.94 (s, 1H). MS (EI) m/z 279/281/283 (M+.). Anal. Calcd for C6H3Br2NS: C, 25.65; H, 1.08; N, 4.99. Found: C, 26.04; H, 1.18; N, 4.86.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:19]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:15]([C:12]2[CH:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=3)=[N:10][CH:11]=2)[OH:16])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: OC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carbaldehyde (1.0 g, 3.96 mmol) in THF (6 mL) was added cyclopentylmagnesium bromide (2.97 mL of a 2.0M solution in THF, 5.95 mmol). The solution was stirred at 0° C. for two hours. The mixture was quenched with saturated aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methanol (1.0 g) as a red oil.