Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[S:6][C:5]4=[N:7][CH:8]=[C:9]([I:10])[N:4]4[N:3]=3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1nn2c(I)cnc2s1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 115 °C
Yield: 47.5 %

Procedure:
To a suspension of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.262 g, 0.794 mmol, 1 eq) in 1,4-dioxane (13 mL), 4-[2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.413 g, 0.953 mmol, 1.2 eq), Cs2CO3 (0.517 g, 1.588 mmol, 2 eq), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.079 mmol, 0.1 eq) and water (6 ml) were added. The resulting mixture was heated at 115° C. overnight. Solvents were removed and the crude was purified in an (solute Flash Si II column (25 g silica gel, 10%-21% EtOAc in c-hexane) to give the desired product (0.21 g). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.98 min, [M+H]+ m/z 557.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]([NH:28][CH3:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([N:28]([CH3:29])[C:8](=[O:10])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:1])([CH3:12])[O:6]2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:30][CH:31]=1
Reactant: CNC(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C(=O)C=C1OC(C)(C)OC1=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (0.936 g, 5.43 mmol) in dry acetonitrile (10 ml) was treated successively with [1-(4-chlorobenzyl)-2-(4-chlorophenyl)-ethyl]-methylamine (1.60 g, 5.43 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP®) (3.11 g, 5.98 mmol) and triethylamine (0.83 ml, 5.98 mmol). After 3 h at 22° C., the clear solution was diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 7:3) gave 2.35 g (97% yield) of the title amide as white needles; mp 109° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): mixture of rotamers; 1.62 and 1.69 (6H, 2 s, CH3), 2.75 and 2.97 (3H, 2 s, NCH3), 2.8-2.9 (4H, m, CH2), 4.15 (1H, m, CH), 5.44 and 5.89 (1H, 2 s, CH), 7.05-7.3 (8H, m, aromatics). Anal. calcd for C23H23C12NO4: C, 61.62; H, 5.17; N, 3.12. Found: C, 61.39; H, 5.25; N, 3.22.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:15][CH:16]=1
Reactant: O=c1c2cc(Br)ccc2ccn1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4ccn(Cc5ccc(F)cc5)c(=O)c4c3)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a degassed solution of 7-bromo-2-(4-fluorobenzyl)isoquinolin-1(2H)-one (149 mg, 0.45 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol) in 1,4-dioxane (5 mL) and water (300 μl) was added Cs2CO3 (195 mg, 0.60 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (19 mg, 0.03 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature for 3 h. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide 5-(2-(4-fluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (140 mg, yield: 75%). (M+H)+: 628.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]C)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].O.CO>C1COCC1.Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)c(Cl)c4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 60.9 %

Procedure:
Methyl 7-(4-((3,4-dichlorophenyl) carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (17 mg, 0.034 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.041 mL, 0.21 mmol), water (200 μL) and methanol (200 μL). After stirring for 2 hours, the reaction was diluted with 2N HCl and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (10 mg, 61% yield). 1H NMR (400 MHz, CD3OD) δ 8.1 (d, 1H), 8.0 (d, 2H), 7.70 (s, 1H), 7.62 (dd, 1H), 7.48 (d, 1H), 7.20 (d, 2H), 6.41 (s, 1H), 4.2-4.35 (m, 2H), 3.82 (bt, 1H), 2.35-2.40 (m, 1H), 2.10-2.15 (m, 1H).
Reaction SMILES: C[C:2]1[C:3](C)=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[CH:8]=[C:7]([CH2:13][CH2:14][CH3:15])[C:6]=2[C:16]#[C:17]CO.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:9]1[CH:8]=[C:7]([CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[CH:17])=[C:5]2[C:10]=1[CH:11]=[CH:2][CH:3]=[N:4]2
Reactant: CCCc1cc(F)c2cc(C)c(C)nc2c1C#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1c(CCC)cc(F)c2cccnc12
Temperature: 120 °C
Yield: 67.1 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-7-propyl-8-quinolylacetylene (390 mg, 1.44 mmol) and NaOH (88.0 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 30 mL Schlenk tube equipped with a reflux condenser and the air inside the flask was replaced with Ar. 5.0 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 206 mg of 5-fluoro-7-propyl-8-quinolylethyne as a yellow solid (yield: 66.6%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:8]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[CH2:35]Br>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][C:28]3[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:8]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccco1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Product: COc1ccc(C(=O)O)c(CN2CCC(c3cn(Cc4ccco4)c4ccc(OC)cc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.17 mmol) of 1-furan-2-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole and 0.057 g (0.22 mmol) of 2-bromomethyl-4-methoxy-benzoic acid methyl ester. After standard work-up and purification by chromatography using a C18 column, 0.029 g (36% of yield) of the expected acid were obtained.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:16][CH3:17])[CH:10]=2)[N:5]=1.Br[CH2:19]B1OC(C)(C)C(C)(C)O1.F.[Na]>O.O1CCCC1>[CH3:17][O:16][C:9]1[CH:8]=[CH:7][C:6]2[N:5]=[C:4]3[CH2:19][O:15][CH2:14][C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)c(CO)cc2c1
Reactant: CC1(C)OB(CBr)OC1(C)C
Agent: F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc3c(cc2c1)COC3
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.6 %

Procedure:
To the mixture of sodium hydride (61%, 250 mg, 6.4 mmol) and tetrahydrofuran (25 ml), (2-chloro-6-methoxy-quinolin-3-yl)-methanol (1.4 g, 6.4 mmol) synthesized in Example 16 was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at room temperature for 40 minutes. To the reaction mixture, 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92%, 700 mg, 2.9 mmol) synthesized in Production Example 2 was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at 50° C. (an outer temperature) for 5 hours. After cooling the reaction mixture to 0° C. (an outer temperature), sodium hydrogen fluoride (580 mg, 9.3 mmol) was added to the reaction mixture at the same temperature, followed by the dropwise addition of water (20 ml) at the same temperature. After stirring the reaction mixture for 15 minutes at room temperature, the solvents were evaporated under reduced pressure. Acetone was added to the obtained residue, followed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Ethyl acetate was then added to the obtained residue, followed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. The mixed solvent of ethyl acetate-diethyl ether (1:4) was added to the obtained residue, followed by filtration. The crystals precipitated in the filtrate were collected, thereby obtaining the entitled compound (260 mg). The solvents were evaporated under reduced pressure from the filtrate, and ethyl acetate was added to the obtained residue and then heated to 60° C., resulting in the precipitation of crystals. The crystals were collected, thereby obtaining the entitled compound (250 mg (510 mg in total), 53%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.Br[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH2:19][NH:20][C:21](=[O:23])[OH:22]>>[O:11]1[CH:12]=[CH:13][C:9]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[CH2:19][NH:20][C:21](=[O:22])[OH:23])=[CH:10]1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: O=C(O)NCc1cccc(Br)c1
Product: O=C(O)NCc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 5-(i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan was reacted with the (3-bromobenzyl)carbamic acid.tert-butyl to give [3-(furan-3-yl)benzyl]carbamic acid.tert-butyl (yield: 96%).
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCCCCCc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-n-hexylaniline (49.1 grams, 0.283 moles), 1-fluoro-4-nitrobenzene (13.3 grams. 0.094 moles) and anhydrous methyl sulfoxide (80 ml). The contents of the flask were heated at 100° C. for 4 days; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml). The ether extract was washed with water (4×100 ml) followed by brine (3×50 ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a brown liquid. The brown liquid was recrystalized from hexane (500 ml) to yield 15.0 grams of product as a yellow solid. 1H NMR (CDCl3) δ 8.1(d, 2H), 7.2(d, 2H), 7.15(d, 2H),6.9(d, 2H), 6.3(bs, 1H), 2.6(t, 2H), 1.6(pent, 2H), 1.2-1.4(m, 6H), 0.9(t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([F:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([F:19])=[C:4]([F:20])[C:3]([F:21])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c(F)c1F
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)c(F)c2F)c1[N+](=O)[O-]
Yield: 57 %

Procedure:
Method H was used with 4-(5-amino-2,3,4-trifluorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound (140 mg, 57%). 1H NMR δ (DMSO): 6.26 (d, 1H, Hpy,5, J=5.5 Hz), 7.35 (s, 2H, NH2), 7.55 (t, 1H, Harom,6′, J=6.5 Hz), 7.66 (d, 1H, Harom), 7.71 (t, 1H, Harom,5″, J=8.0 Hz), 7.91 (s, 1H, Harom,2″), 8.00 (d, 1H, Harom), 8.08 (d, 1H, HPy,6, J=5.5 Hz), 10.63 (s, 1H, NHamide). 19F NMR δ (DMSO): −56.28 (s, 3F, CF3), −141.42 (d, 1F, aromF, J=21.5 Hz), −152.31 (d, 1F, aromF, J=21.5 Hz), −156.04 (t, 1F, F3, J=21.5 Hz).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(OCC)(=O)C.CCCCCC>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([OH:16])=[O:15]
Reactant: CCCCCC(C(=O)OCC)(C(=O)OCC)c1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(C(=O)O)c1ccc(OC)cc1OC
Temperature: 25 °C
Yield: 85.1 %

Procedure:
10.0 ml (20.0 mmol) of a 2 N aqueous aqueous solution of sodium hydroxide were added to a solution of 1.30 g (3.55 mmol) of diethyl 2-(2,4-dimethoxyphenyl)-2-pentylmalonate [prepared as described in step (i) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was freed from ethanol by distillation under reduced pressure, and the resulting residue was acidified with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was disssolved in 20 ml of xylene, and the solution was heated under reflux for 80 minutes. At the end of this time, the reaction mixture was cooled to room temperature, after which it was purified by column chromatography through 50 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:3 to 1:1 by volume as the eluent, to give 805 mg (yield 85%) of the title carboxylic acid derivative as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:4][CH:3]=1.[CH2:34]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1nccc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1nccc(-c2sc(C3CCN(C)CC3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 85 %

Procedure:
4-(4-Fluorophenyl)-2-(piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl) thiazole (575 mg 1.25 mmol) is dissolved in MeOH (12 ml) and treated with an aqueous 36%-solution of formaldehyde (0.2 ml 2.5 mmol and NaBH4 (95 mg 2.5 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5 to 90/9/1) to yield the title compound (600 mg 85%) as pale yellow foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:30][C:31]([OH:35])([C:33]#[CH:34])[CH3:32].C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[CH3:30][C:31]([OH:35])([C:33]#[C:34][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:32]
Reactant: CC(O)(c1ccc(-c2ccc(S(=O)(=O)c3ccccc3)c(Cl)c2)cc1)C(F)(F)F
Reactant: C#CC(C)(C)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(O)C#Cc1cc(-c2ccc(C(C)(O)C(F)(F)F)cc2)ccc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A 20 mL vial was charged with 2-(3′-chloro-4′-(phenylsulfonyl)-4-biphenylyl)-1,1,1-trifluoro-2-propanol (0.300 g, 0.680 mmol, Example 19), 2-methyl-3-butyn-2-ol (0.099 mL, 1.021 mmol, Sigma-Aldrich, St. Louis, Mo.), potassium carbonate (0.235 g, 1.701 mmol), 2 mL of dimethylacetamide, 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (XPhos) (9.73 mg, 0.020 mmol, Strem Chemical Inc, Newburyport, Mass.), and tris(dibenzylideneacetone)dipalladium (0) (0.021 g, 0.020 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and heated at 100° C. for 2 h. After that time, the mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 40% EtOAc in hexane) to give 2-methyl-4-(4-(phenylsulfonyl)-4′-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol (0.035 g) as a mixture of two enantiomers.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:10]=1[NH2:11]>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:10]=1[NH:11][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1c(C)cccc1C

Procedure:
A solution of 1-propanesulphonyl chloride (25 ml) in toluene (50 ml) was added during 15 minutes to a stirred solution of 2,6-dimethylaniline (55 ml) in toluene (400 ml). The mixture was stirred and boiled under reflux for 20 hours, then cooled and filtered. The toluene solution was washed with dilute hydrochloric acid (3 times) and water, then extracted (3 times) with dilute sodium hydroxide solution. The aqueous alkaline solution was acidified with dilute hydrochloric acid, and the product collected by filtration, washed with water and dried. Crystallisation from toluene/60°-80° petrol gave 2',6'-dimethyl-1-propanesulphonanilide as buff coloured crystals (28.0 g, 55%), melting point 72°.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCCO
Solvent: ClCCl
Product: OCCCCCCCCCCOCc1ccccc1
Yield: 65 %

Procedure:
To a stirred suspension of decane-1,10-diol (3 g, 17.21 mmol), benzyl bromide (2.25 ml, 18.94 mmol) and Ag2O (5.98 g, 25.82 mmol) in dry DCM (50 ml) were added, the reaction mixture was refluxed overnight, then the Ag2O was filtered off. The crude product was purified by silica gel column (10% EtOAc in Hexane) to afford 10-(benzyloxy)decan-1-ol as a gummy colorless liquid (2.96 g, 65%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[C]=O.Cl>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:1]([OH:2])=[O:4])=[C:10]([OH:14])[CH:9]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [C]=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(F)cc1O
Temperature: 200 °C
Yield: 52.3 %

Procedure:
Potassium carbonate (51.6 g, 373 mmol) was dried by heating at 200° C. for 12 hours. This was treated with 3-fluorophenol (16.5 g, 147 mmol) in a sealed container which was then pressurized with carbon monoxide at 61.2 bar. The reaction was heated to 175° C. for 5 hours. Subsequently, the reaction mixture was dissolved in water, acidified with concentrated hydrochloric acid, and filtered. The solid was washed with water, then hexanes. The solid was then dissolved in EtOAc, dried over magnesium sulfate, and concentrated to give 12 g of solid. This crude solid was purified by flash chromatrography using CHCl3/MeOH/HOAc 98:1:1 to give 11 g of a white solid which was recrystallized from toluene to give 9.5 g of the product as needles.