Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7]C(O)=O)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.C1(C=CC(O)=CC=1)O.C(=O)=O>[Cu]>[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C=O
Agent: Oc1ccc(O)cc1
Solvent: c1ccc2ncccc2c1
Product: C=Cc1ccc(O)cc1
Yield: 11.76 %

Procedure:
Para-vinylphenol was prepared as follows. 15.6 g of p-hydroxycinnamic acid were mixed to a slurry with 15 ml quinoline, 0.6 g copper turnings and 1.1 g hydroquinone. The mixture was heated by an oil bath at 200° C. for 15 minutes after which time the evolution of CO2 had almost ceased. The reaction mixture was then cooled and distilled under rotary pump vacuum, the fraction collected between 60° and 80° C. being p-vinylphenol and quinoline. (Bpt. Quinoline=114° C./15 mm Hg; p-vinylphenol=115° C./16 mm Hg). The distilled fraction was taken up into warm diethyl ether, the solution neutralised by successive washing of N HCl and distilled water and then dried by MgSO4. After removal of the solvent, the residue was redissolved by warm petroleum ether (40°-60° C.). On cooling 1.36 g of colourless, platey crystals were obtained. Yield=11.76%. These were recrystallised from the same solvent prior to copolymerisation.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:31].[Li+]>C(COC)OC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:31])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(F)c1)C(=O)O

Procedure:
Analogously to Example 1i), 3.7 g (8.95 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(m-fluorophenylmethyl)-dihydrofuran-2-(3H)-one in 140 ml of dimethoxyethane are hydrolysed with 35.8 ml of 1M lithium hydroxide solution. Extraction of the evaporation residue of the reaction mixture from a mixture of ice, 120 ml of sat. ammonium chloride solution and 240 ml of 10% citric acid solution with a large amount of methylene chloride (solubility!) yields the title compound: tRet (I)=14.6 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH:16]([CH3:18])[CH3:17])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:19].[C:20]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:32][C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=3)[C:25]([NH:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:34])[C@@H:12]([CH:16]([CH3:17])[CH3:18])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:19]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC(C)[C@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[C@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Yield: 46.7 %

Procedure:
(S)-(4-Amino-3-fluorophenyl)(3-isopropylpiperazin-1-yl)methanone (0.754 mmol, 200 mg), N-tert-butyl-3-(chloromethyl)benzamide (0,754 mmol, 170 mg), potassium carbonate (1.508 mmol, 208 mg) and sodium iodide (0.075 mmol, 11.30 mg) were dissolved in acetonitrile (20 mL) and heated at reflux for 3 hours. The reaction was concentrated under vacuum and the crude material dissolved in ethyl acetate and washed with water, dried over sodium sulphate and concentration under vacuum. The crude residue was then purified by column chromatography (eluting with dichloromethane to dichloromethane/methanol (1% to 5%)) to give the title compound (160 mg) as an off white solid. MS (ESI) m/z 456.4 [M+H]+
Reaction SMILES: Cl.[CH:2]1([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][CH2:26][C:20]=2[C:19]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])[CH2:25][CH2:26][C:20]=2[C:19]=1[NH:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(CC2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CC4CCCCC4)cc3)c2CC1)C(F)(F)F
Temperature: 90 °C
Yield: 63.2 %

Procedure:
Under a nitrogen atmosphere, add 4-cyclohexylmethyl-benzylamine hydrochloride (352 mg, 1.47 mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol), palladium(II) acetate (52.7 mg, 0.235 mmol), BINAP (293 mg, 0.47 mmol) and cesium carbonate (1.53 g, 4.7 mmol) to toluene (20 mL). Heat the mixture at 90° C. for 12h. Cool the mixture to room temperature and dilute with EtOAc (25 mL). Filter the solids through cellulose (20g) and concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel (45g RediSep column) eluting with hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to provide 7-chloro-6-(4-cyclohexylmethyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (354 mg, 63%). MS (APCI) m/z: 479 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]1[CH:25]=[C:26]([CH2:34][OH:35])[CH:27]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:29]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:29]=1)[CH:34]=[O:35]
Reactant: CS(=O)(=O)c1cc(F)cc(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)cc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (530 mg, 1.21 mmol) was added in one portion to [3-fluoro-5-(methylsulfonyl)phenyl]methanol (225 mg, 1.10 mmol) in DCM (20 mL) at 22° C. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM (50 ml) and poured into saturated aqueous sodium bicarbonate (30 mL) containing sodium thiosulfate (1219 mg, 7.71 mmol). The resulting suspension was stirred for 10 minutes before separating the layers. The organic layer was washed with water (1×50 mL), dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 3-fluoro-5-(methylsulfonyl)benzaldehyde (168 mg, 75%) as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]([CH2:22][CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1>O>[CH3:21][C:17]1[CH:16]=[C:15]([N:14]([CH2:12][CH3:13])[CH2:22][CH3:23])[CH:20]=[CH:19][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1
Product: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1

Procedure:
A mixture of phthalic anhydride (60 g.), N,N-diethyl-m-toluidine (162.8 g.), aluminum chloride (120 g.) and chlorobenzene (360 ml.) was heated (75°-95° C.) during one and one-half hours, then diluted with water (200 ml., then more). More chlorobenzene (200 ml.) was added and the chlorobenzene layer was separated and steam distilled. Addition of sodium hydroxide solution (10% to a solution of the residue in dilute sulfuric acid (20%, 250 ml.) afforded 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][NH:24][CH2:23][CH2:22]2)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([CH2:2][CH:3]1[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]1)[CH2:23][CH2:22]2)=[O:16]
Reactant: COC(=O)c1cccc2c1CNCC2
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1CN(CC1COc3ccccc3O1)CC2
Temperature: 140 °C

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.88 mmol) and 1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.88 mmol) in DMF (10 ml) was added K2CO3 (0.61 g, 4.41 mmol). The reaction mixture was heated under microwaves at 140° C. for 10 min. Water was then added and the mixture extracted with DCM (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([F:20])[CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1CCCNC1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[CH2:36].C([O-])(=O)C.[Na+]>CN1CCCC1=O.[Pd]Cl>[F:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:36]=[CH:35]/[C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[F:32])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:15]1
Reactant: C=Cc1ccccc1F
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccccc1CN1CCCC(F)C1
Agent: Cl[Pd]
Agent: CC(=O)[O-]
Agent: FC1CCCNC1
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccc(/C=C/c2ccccc2F)cc1)c1ccccc1CN1CCCC(F)C1
Temperature: 130 °C

Procedure:
1-{2-[(4-Bromophenyl)sulfonyl]benzyl}-3-fluoropiperidine (prepared according to the methods of Example 75 Step 1 followed by Example 74 using 3-fluoropiperidine; 63 mg, 0.152 mmol), 2-fluorostyrene (36 μL, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and palladium(I) chloride (1 mg) were combined in 1-methyl-2-pyrrolidinone (0.5 mL) and heated for 2 hours at 130° C. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed further with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 30% ethyl acetate/isohexane, to give the title compound. δH (400 MHz, d6 DMSO): 8.19 (1H, d, J=6.3 Hz), 8.00-7.97 (2H, m), 7.86-7.82 (2H, m), 7.77 (4H, s), 7.48-7.34 (3H, m), 7.23-7.19 (2H, m), 5.15 (1H, d, J=49 Hz), 4.72 (1H, d, J=13.4 Hz), 4.45-4.40 (1H, m), 3.79-3.73 (1H, m), 3.55-3.51 (1H, m), 3.45-3.32 (2H, m), 3.20-3.14 (1H, m), 1.99-1.93 (2H, m), 1.73 (1H, d, J=12.1 Hz). m/z (ES+) 454 [MH+].
Reaction SMILES: C([O-])(=O)C.[C:5]([O-:13])(=[O:12])[CH:6]([CH2:8][C:9]([O-:11])=[O:10])[SH:7].[Na+].[Na+].C([O-])(=O)C.[Na+]>>[C:5]([OH:13])(=[O:12])[CH:6]([CH2:8][C:9]([OH:11])=[O:10])[SH:7]
Reactant: O=C([O-])CC(S)C(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CC(S)C(=O)O

Procedure:
Another synthesis for forming thiomalic acid is by the reaction of thioacetic acid and maleic acid as cited in Flett and Garner's, "Maleic Anhydride Derivatives", (J. Wiley, New York 1952) page 225. The example given here uses thioacetic acid plus maleic acid to give mercaptosuccinic acid acetate having the formula ##STR1## and the yield is 83% of that required by theory for the latter but no yield is given for the subsequent alkaline hydrolysis of this acetate to disodium thiomalate and sodium acetate and the eventual acidification to give thiomalic acid. This procedure is impractical in that the thioacetic acid preparation is expensive and is not commercially available on a large scale at an economical price, and thus is a drawback to this process. Moreover, once thiomalic acid is obtained by alkaline hydrolysis of the acetate and acidification, it must still be isolated from the water solution containing inorganic salts, just as in the sulfide process of the British patent already discussed.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:15]Br>CC(O)=O>[F:14][C:2]([F:1])([F:13])[C:3]1[NH:4][C:5]2[C:11]([Br:15])=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: BrBr
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Solvent: CC(=O)O
Product: Nc1ccc2nc(C(F)(F)F)[nH]c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 3.2 g (16 mmol) of 2-trifluoromethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.34 ml (6.6 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (10% MeOH/CHCl3) to yield 1.7 g (6.2 mmol, 94%) of the desired product.
Reaction SMILES: Cl.Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Mg].[F:11][C:12]([F:29])([F:28])[C:13]1[CH:26]=[CH:25][C:24]2[O:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:27])[C:15]=2[CH:14]=1>O1CCCC1>[CH3:9][N:6]1[CH2:7][CH2:8][CH:3]([C:16]2([OH:27])[C:15]3[CH:14]=[C:13]([C:12]([F:28])([F:29])[F:11])[CH:26]=[CH:25][C:24]=3[O:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:4][CH2:5]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccccc2oc2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Oc3ccc(C(F)(F)F)cc32)CC1
Reaction time: 1 h

Procedure:
The Grignard reagent from 68 g. (0.4 m.) of 4-chloro-N-methylpiperidine hydrochloride and 9.7 g. (0.4 m.) of magnesium turnings in a total volume of 250 ml. of tetrahydrofuran is obtained following the procedure of Example 3. After all the halide is added, 75.6 g. (0.287 m.) of 2-trifluoromethylxanthone is added portionwise and refluxing/stirring are continued for one hour under nitrogen. The reaction mixture is quenched on ice-water-ammonium chloride to give 9-(1-methyl-4-piperidyl)-2-trifluoromethylxanthene-9-ol, m.p. 179°-183° C.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH:12]=1)[CH2:10]Br.O>C(O)C.C(OCC)(=O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH2:10][C:1]#[N:2])[CH:12]=1
Reactant: [C-]#N
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: N#CCc1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
1.95 g (30 mmol) of potassium cyanide is added to a solution of 5.14 g (20 mmol) of 5-fluoro-2-trifluoromethylbenzyl bromide in 45 ml of ethanol/8 ml of water, and it is stirred for 64 hours at room temperature. The reaction solution is diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. The organic phase is washed with water, dried and concentrated by evaporation. The remaining residue is purified by bulb tube distillation and recrystallized. Yield: 3.6 g (89%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Cl:14][C:15]1[C:16]([CH2:26]Cl)=[N:17][CH:18]=[C:19]([CH:25]=1)[C:20]([O:22]CC)=[O:21].[OH-].[Na+].Cl>CN(C=O)C.C1COCC1.O>[Cl:14][C:15]1[C:16]([CH2:26][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:17][CH:18]=[C:19]([CH:25]=1)[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnc(CCl)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(COCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of 2,2,2-trifluoroethanol (2.66 g, 26.6 mmol) and cesium carbonate (5.78 g, 17.7 mmol) in DMF (22 mL) is added ethyl 5-chloro-6-(chloromethyl)nicotinate hydrochloride (1.20 g, 4.44 mmol). After stirring at rt for 1 hour, 2 M aqueous sodium hydroxide solution (10 mL), water (20 mL), and THF (20 mL) are added to the mixture. After stirring at 60° C. for 2 hours, the mixture is acidified by 2 M hydrochloric acid (pH 4). The organic solvent is removed by evaporation, and the residual aqueous layer is extracted with EtOAc/hexane. The separated organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo to give 1.19 g (>99%) of the title compound as brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added methanesulfonyl chloride (0.20 ml, 0.25 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (46 mg, 77%) as white solid. MS m/e: 476 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.F[CH:29](F)[N:30]1[CH:34]=[C:33](I)[C:32](C)=[N:31]1.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.COCCOC>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[CH:4][N:3]=1
Reactant: Cc1nn(C(F)F)cc1I
Reactant: COC(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(-c3cnn(C)c3)cnc2N)cc1F
Temperature: 100 °C

Procedure:
A mixture of crude methyl 4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-fluorobenzoate (712 mg, 1.912 mmol), 1-(difluoromethyl)-4-iodo-3-methyl-1H-pyrazole (740 mg, 2.87 mmol), PdCl2(dppf) (70.0 mg, 0.096 mmol), DME (7.899 mL), and 2M Na2CO3 (3.95 mL) was heated at 100° C. overnight. After adding Na2SO4 followed by dilution with EtOAc, the reaction mixture was filtered off and the resulting volatile materials were concentrated in vacuo. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc in DCM. LCMS (m/z): 491.1 (MH+), 0.64 min
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[C:41]=1B(O)O>>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[C:42]([OH:46])=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1c(O)cccc1Cl
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O)cccc5Cl)c4)nn23)CC1
Yield: 81 %

Procedure:
Prepared from (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (2-chloro-6-hydroxyphenyl)boronic acid using the same procedure as intermediate 168 in 81% yield. 1H NMR (400 MHz, CDCl3) [note: 4H of piperidine and phenolic —OH not observed] δ 8.13-8.06 (m, 1H), 7.97 (s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.26-7.20 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.89-6.77 (m, 1H), 6.06-5.90 (m, 1H), 5.39 (dd, J=17.1, 1.5 Hz, 1H), 5.29-5.20 (m, 1H), 5.15-5.04 (m, 1H), 3.99 (d, J=4.8 Hz, 2H), 3.76 (s, 3H), 2.63 (br. s., 3H), 2.07-1.91 (m, 3H), 1.79-1.65 (m, 1H), 1.35 (s, 3H), 1.25 (s, 9H). LCMS (M+1)=633.3.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=3[OH:12])=[O:24])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1O

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 1-hydroxy-2-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.95-2.04 (m, 2H), 2.15-2.27 (m, 1H), 2.33-2.46 (m, 3H), 2.56-2.64 (m, 1H), 3.48-3.90 (m, 6H), 4.42-4.53 (m, 1H), 7.05-7.28 (m, 1H), 7.37-7.57 (m, 2H), 7.67-7.78 (m, 1H), 7.81-7.90 (m, 1H), 8.34-8.44 (m, 1H); MS (APCI/NH3) m/z 323 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([O:15][Si](C(C)(C)C)(C)C)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
(3R,5S)-N-Boc-3-tert-Butyldimethylsiloxy-5-ethynyl-pyrrolidine (700 mg, 2.15 mmol) (Example 99B above) was dissolved in a mixture of THF (20 mL) and H2O (1 mL). TBAF (1M in THF) (Aldrich) was added (2.15 mL, 2.15 mmol) at 0° C. and the reaction mixture was allowed slowly to warm up to room temperature. After 21 hr at room temperature and 2 hrs at 50° C. the mixture was concentrated to a small volume diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated. (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes gradient. (Yield 390 mg, 81%).