Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@:11]1([C:26]([O:28]C)=[O:27])[CH2:13][C:12]1([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@:11]1([C:26]([OH:28])=[O:27])[CH2:13][C:12]1([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@]1(c2ccc3ccccc3c2)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)[C@@]1(c2ccc3ccccc3c2)CC1(c1ccccc1)c1ccccc1
Yield: 61 %

Procedure:
To a round-bottom flask at room temperature was added (R)-methyl 1-(naphthalen-2-yl)-2,2-diphenylcyclopropanecarboxylate (18.5 mmol, 7.0 g, 1.0 equiv) in dry DMSO (50 mL). t−BuOK (41.0 mmol, 4.6 g, 2.2 equiv) was added in several portions over 30 minutes under argon. The reaction was monitored by TLC technique until the starting material was consumed completely. The reaction mixture was cooled with ice bath and acidified by saturated ammonium chloride aqueous (15 mL), followed by a slow addition of 1 N HCl (40 mL) with vigorous stirring until the pH value reached 3-4. Sticky solid precipitate was collected by filtration, washed with water (3×5 mL), dissolved in ethyl acetate (150 mL), washed with brine (3×10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 4:1 mixture of hexanes/ethyl acetate to provide the desired product as a white solid (4.1 g, 61% yield. mp: 195-196° C.; [α]20D −361.7° (c=1.0, CHCl3); 1H NMR (400 MHz; CDCl3) δ 7.80-7.76 (m, 3H), 7.65-7.59 (m, 3H), 7.53-7.46 (m, 3H), 7.42-7.34 (m, 3H), 7.11-7.09 (m, 2H), 7.0-6.9 (m, 3H), 2.73 (d, J=5.2 Hz, 1H), 2.65 (d, J=5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.4, 141.5, 139.1, 133.1, 132.7, 132.3, 130.3, 130.1, 129.8, 128.6, 128.4, 127.7, 127.6, 127.5, 126.9, 126.7, 126.2, 125.8, 125.7, 42.7, 23.4; IR (neat): 3058, 1687, 1448, 1300; HRMS (APCI) calcd for C26H21O2 (M+H)+ 365.15361. found 365.15349; HPLC (to improve the separation, the product was converted to the corresponding methyl ester prepared using dimethylsulfate/KOH in tetrahydrofuran under reflux), HPLC (ODH, 0.5% isopropanol in hexane, 1.0 mL/min, 1 mg/mL, 30 min, UV 254 nm) retention times of 8.6 min (major) and 9.6 min (minor), >99% ee.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:14])[C:11]([CH3:13])=[CH2:12]>C(O)C>[NH2:14][C:10]1[CH:11]([CH3:13])[CH2:12][N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: C=C(C)C#N
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2ccccc2)N=C1N
Reaction time: 0.17 h

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 200 ml. of absolute ethanol, then 37.4 g. of phenylhydrazine is added followed in 10 minutes by 20.1 g. of methacrylonitrile. The reaction mixture is refluxed for 4 hours then is evaporated to near dryness in vacuo. Water is added to the residue to separate an oil. The oil crystallizes on standing. The solid is dissolved in dichloromethane. The solution is passed through a short column of a hydrous magnesium silicate. The column effluent is evaporated to give an oil. The oil is crystallized from acetone-hexane then is recrystallized from the same solvent pair to give 20.88 g. of the desired product as colorless crystals, m.p. 83°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@:13]([OH:27])([CH3:26])[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.CN>C(O)C.CO>[NH2:15][CH2:14][C@@:13]([CH3:26])([OH:27])[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: C[C@](O)(CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)CN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CO
Solvent: CCO
Product: C[C@@](O)(CN)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a solution of 2-[(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl]-1H-isoindole-1,3(2H)-dione (278 mg, 0.6 mmoles) in ethanol (5 ml) was added aqueous methylamine (40% wt. solution in water, 6 ml). The mixture was stirred at room temperature for 24 h and then concentrated in vacuo to leave a crude yellow glass. This glass was dissolved in methanol (2 ml), added to an Isolute Flash SCX cartridge (2 g), washed with methanol (25 ml) and 7N ammonia in methanol (25 ml). The methanolic ammonia was concentrated in vacuo to give the title compound as a yellow glass (165 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCCC.C([Li])CCC.O([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])S(C(F)(F)F)(=O)=O>C1COCC1>[CH:26]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)([CH3:28])[CH3:27]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxazole (2.1 g) in THF (90 mL) was added dropwise n-butyllithium hexane solution (1.6M, 19.7 mL) at −78° C. The reaction mixture was stirred at 0° C. for 10 min under nitrogen atmosphere, and triisopropylsilyl triflate (8.5 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.7 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][C:6]1=[O:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]([CH3:15])=[CH:7][C:6]3=[O:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1cc(=O)n(CCCCl)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
A suspension of 1-(3-chloropropyl)-4-methyl-2(1H)-quinolinone (VI-4) (455 mg, 1.93 mmol), 3-(4-piperidinyl)-1H-indole (350 mg, 1.75 mmol) and sodium hydrogencarbonate (220 mg, 2.63 mmol) in dry dimethylformamide 6 ml was allowed to react at 90 ° C. for 15 hours. Ice-water was poured into the reaction mixture and then the separated solid was filtered off by aspiration. The solid was dissolved in chloroform, then dried and the solvent was distilled off under the reduced pressure. The residue was dissolved in developing solvent (chloroform: methanol=9:1) and purified by silica gel column chromatography. After removing the first eluted impurity, a colorless solution was collected and the solvent was distilled off to give the desired product (VII-4) (450 mg) as a pale yellow solid (yield 64.4%, mp 74°-77 ° C.).
Reaction SMILES: [OH-].[Na+].CO[C:5]([NH2:7])=[NH:6].OS(O)(=O)=O.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1>O>[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)(=[NH:6])[NH2:7]
Reactant: O=C(O)CCC1CCNCC1
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)N1CCC(CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 50.9 %

Procedure:
20 ml of 2 N sodium hydroxide was stirred with ice-cooling, and 3.4 g of o-methylisourea sulfate and 3.1 g of piperidine-4-propionic acid were added to the aqueous sodium hydroxide solution. To the mixture was then added 5 ml of water, and the resulting mixture was stirred at room temperature for 19 hours. The product precipitated was separated by filtration and washed with a small amount of cold water three times, then with acetone and finally with ether to obtain 2.0 g of 1-amidino-4-piperidinepropionic acid as colorless crystals having a melting point of 294° C. (decomposed).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O1CCOCC1.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]>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1Br
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
A mixture of 2-bromobenzonitrile (5.1 g, 28 mmol), 2-fluorobenzeneboronic acid (4.9 g, 35 mmol) and potassium fluoride (5.37 g, 92 mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 10 min. This mixture was then treated with tris(dibenzylideneacetone)dipalladium(0) (510 mg, 0.56 mmol) followed by tri-tert-butylphosphine (5.6 ml of a 0.2M solution in 1,4-dioxane, 1.12 mmol) and the reaction was stirred at ambient temperature for 15 min. The resulting slurry was then heated at 50° C. for 30 min in order to consume remaining starting materials and then cooled to ambient temperature. The reaction mixture was filtered, washing the filter-cake with tetrahydrofuran (50 ml). The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane on a gradient of ethyl acetate (5-10%) gave 2′-fluorobiphenyl-2-carbonitrile as a pale yellow solid (5.5 g, 100%): δH (360 MHz, CDCl3) 7.19-7.29 (2H, m), 7.40-7.52 (4H, m), 7.65 (1H, ddd, J 8, 8 and 1), 7.79 (1H, dd, J 8 and 1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][C:11]1[N:12]=[C:13]([C:22](OCC)=[O:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCO>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:22]([C:13]1[S:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH3:10])[N:12]=1)=[O:23])[CH2:3]2
Reactant: CCOC(=O)c1nc(C)c(-c2ccccc2)s1
Reactant: N[C@H]1CN2CCC1CC2
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@H]2CN3CCC2CC3)sc1-c1ccccc1
Reaction time: 48 h
Yield: 55 %

Procedure:
The freebase of (R)-3-aminoquinuclidine (1.0 g, 5.02 mmol, 2.26 eq) dissolved in THF (˜5 mL) is added to a solution of the product from Step 89c (0.55 g, 2.22 mmol, 1 eq) in 10 mL EtOH. The mixture is heated under reflux. After 48 h, the mixture is cooled and concentrated in vacuo. The residue is purified by silica gel chromatography using a Biotage Flash 40S column (90:9:1 CHCl3/MeOH/NH4OH) to provide N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-methyl-5-phenyl-1,3-thiazole-2-carboxamide (0.40 g, 55%) as a yellow oil. The p-toluenesulfonic acid salt of the product is made and recrystallized from IPA/ether to give the product as light yellow solid. MS (ESI) for C18H21N3OS m/z 328.2 (M+H)+.
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4](=[O:6])=[O:5]>O>[C:4](=[O:1])([OH:6])[O-:5].[Ca+2:2].[C:4](=[O:1])([OH:6])[O-:5]
Reactant: [OH-]
Reactant: O=C=O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])O

Procedure:
In the next step, calcium hydroxide (Ca(OH)2) is added at the downstream end 48 of the second flow channel 36. The sequestered carbon dioxide (CO2), dissolved in the desalinated water, then reacts with the added calcium hydroxide (Ca(OH)2) to produce calcium bicarbonate (Ca(HCO3)2) in accordance with the following equation: Ca(OH)2+CO2→Ca(HCO3)2  (Eq. 3)
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl:22]Cl>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([Cl:22])=[O:19])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: ClCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C(Cl)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
10 g of azobis(isobutyronitrile) are added, with stirring, to 620 g of 4-fluorobenzaldehyde (5 mol tel quel, purity >99 GC[a/a]) under protective gas in a 1 l four-necked flask. The mixture is then heated to an internal temperature of 60° C. and, over the course of 7.5 hours, a total of 354 g of chlorine are introduced. The chlorine is added in an amount of 15 liters per hour. Unreacted chlorine is then blown out with nitrogen, and the reaction mixture is cooled to room temperature. The progress of the reaction is monitored using gas-chromatographic analysis (GC).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH3:23])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:21]=1[CH3:22].ClCCCl.N1C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:40](Cl)=[O:41]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:24])=[C:5]([CH3:23])[C:6]2[O:11][C:10]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:40](=[O:41])[C:39]4[CH:38]=[C:37]([O:36][CH3:35])[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=4)[CH2:19][CH2:20]3)([CH3:12])[CH2:9][CH2:8][C:7]=2[C:21]=1[CH3:22]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(=O)N2CCN(CCC3(C)CCc4c(C)c(OC)c(C)c(C)c4O3)CC2)cc(OC)c1OC
Yield: 62.8 %

Procedure:
A solution composed of 2.0 g (6.02 mmol) of the 3,4-dihydro-6-methoxy-2-[2-(piperazin-1-yl)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran obtained by the process of Example 12, 50 ml of 1,2-dichloroethane and 0.57 g of pyridine was ice-cooled in a nitrogen atmosphere and, to this solution, 1.67 g of 3,4,5-trimethoxybenzoyl chloride was added dropwise. The resultant mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with diethyl ether. The ether layer was dried over anhydrous sodium sulfate. Low-boiling substances were distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 1.99 g of 3,4-dihydro-6-methoxy-2-[2-[4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl]ethyl]-2,5,7,8-tetramethyl-2H-benzopyran [Compound (17)] having the following physical characteristics.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH3:26][NH:27][CH3:28]>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:27]([CH3:28])[CH3:26])[S:8]1(=[O:25])=[O:24]
Reactant: CNC
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CCO
Product: CN(C)CCOCCN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 33% dimethylamine in ethanol to give 2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N,N-dimethylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.157 g, 30%). MS (ES) m/z 397.9 ([M+H]+). HPLC retention time: 7.1 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)c2cc3ccncc3[nH]2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cc3ccncc3[nH]2)cc1
Reaction time: 14 h
Yield: 67.1 %

Procedure:
(4-Methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 98) (225 mg, 0.94 mmol) was dissolved in methylene chloride (15 mL). Manganese dioxide (817 mg, 9.40 mmol) was added and the reaction mixture was stirred for ca. 14 h. The reaction mixture was filtered through diatomaceous earth and the filter cake was washed several times with hot ethanol. The filtrate was concentrated to give a white solid. Drying under vacuum produced (4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (149 mg, 67%) as a white solid: mp 264-268° C. dec.; 1H NMR (300 MHz, CD3OD) δ2.47 (3H, s), 7.18 (1H, s), 7.41 (2H, d, J=7.9 Hz), 7.73-7.75 (1H, m), 7.92 (2H, d, J=8.1 Hz), 8.16 (1H, d, J=5.6 Hz), 8.87 (1H, s); ESI MS m/z 237 [C15H12N2O+H]+; HPLC (Method A) 93.4% (AUC), tR=15.9 min.
Reaction SMILES: [C:1]([O:9]C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+:21]>O1CCCC1>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:21]
Reactant: O=C(Oc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C([O-])c1ccccc1
Yield: 74 %

Procedure:
The procedure of Example 1 was followed using phenyl benzoate (3.96 g, 20 mmol), potassium trimethylsilanolate (2.56 g, 20 mmol), dry tetrahydrofuran (50 mL), and a 5 h reaction time. Potassium benzoate (2.37 g, 74% yield) was isolated as a white solid: 1H NMR (D2O, DSS, 80 MHz) δ 7.4-8.0 (m, Ar--H's, 5H). Anal. Calcd. for C7H5KO2 : C, 52.48; H, 3.15; K, 24.41, Found: C, 50.28, 50.15, 52.45; H, 3.28, 3.36, 3.24; K, 24.80.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([Br:22])=[CH:16][CH:17]=3)[C:12]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])(O)[C:11]=2[CH:10]=1.SC(C)C(O)=O.S(=O)(=O)(O)O>O.CO.C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([Br:22])=[CH:16][CH:17]=3)[C:12]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[C:11]=2[CH:10]=1
Reactant: Cc1ccc(C)c(C2(O)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Reactant: Oc1ccccc1
Agent: CC(S)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(C)c(C2(c3ccc(O)cc3)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
9.5 g of phenol were mixed with 22.2 g of 2,7-dibromo-9-(2,5-dimethylphenyl)fluoren-9-ol, 25 ml of toluene and 0.1 ml of mercapto-propionic acid. 5 ml of concentrated sulfuric acid were subsequently added dropwise. The batch was then stirred at 60° C. for about 2 hours, and finally 100 ml of MeOH and 100 ml of water were added. The solid was filtered off with suction and further purified by stirring with ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1.Br[C:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]([CH:37]2[CH2:40][CH2:39][CH2:38]2)[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:37]1([N:30]2[C:31]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[C:28]([C:15]3[CH:14]=[CH:13][C:12]([O:11][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:17][CH:16]=3)=[N:29]2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2cccnc21
Reactant: Brc1nn(C2CCC2)c2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(Oc2ccc(-c3nn(C4CCC4)c4cccnc34)cc2)nc2cccnc21
Yield: 99.1 %

Procedure:
A mixture of 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3H-imidazo[4,5-b]pyridine (252 mg), 3-bromo-1-cyclobutyl-1H-pyrazolo[4,3-b]pyridine (181 mg), Pd(PPh3)4 (25 mg) and Na2CO3 (266 mg) in DME (5 mL) and water (1 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (282 mg).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]([F:16])([F:15])[F:14])[C@H:10]([CH2:17][OH:18])[CH2:9]1)C1C=CC=CC=1.[ClH:19]>C(O)C.[C].[Pd]>[ClH:19].[OH:18][CH2:17][C@H:10]1[C@H:11]([C:13]([F:16])([F:14])[F:15])[CH2:12][NH:8][CH2:9]1
Reactant: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC[C@@H]1CNC[C@H]1C(F)(F)F
Yield: 99.7 %

Procedure:
In 20 ml of ethanol, is dissolved 2.20 g (8.49 mmol) of trans-1-benzyl-3-hydroxymethyl-4-trifluoromethylpyrrolidine, and 1 ml of conc-hydrochloric acid is added to the solution. A hydrogenation is performed by adding 440 mg of 10% palladium carbon to the above solution at 40° C. and 1 atmospheric pressure. Four hours later, the catalyzer was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1.74 g of the objective substance as a colorless powder (yield 99.7%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[C:6](Cl)[N:5]=1.[C:15]([O:19][C@@H:20]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[CH3:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C@@H:20]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:6]1[N:5]=[C:4]([Cl:3])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1)[CH3:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.58 mmol, 1.2 equiv) was added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (90 mg, 0.483 mmol, 1 equiv) in DMF (2.4 mL) at 0° C. The suspension was stirred at 0° C. for 1 hour, by which time it turned yellow. The reaction was quenched with dilute aqueous sodium chloride (20 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) separated the regioisomers and provided methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (0.111 g, white solid) in 64% yield. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 4.76 (m, 1H), 4.69 (dd, J=9.4, 2.7 Hz, 1H), 4.52-4.41 (m, 2H), 4.02 (s, 3H), 1.26 (s, 9H), 1.05 (d, J=6.6 Hz, 3H). MS m/z 358.2 (M+H)+; Rt-1.00 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(C#N)(C)=O>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(Cl)Cl.O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 150 °C
Yield: 77.8 %

Procedure:
Alternatively, 1-(4-bromophenyl)-2,2,2-trifluoroethanol (0.98 g, 3.86 mmol), m-tolylboronic acid (0.63 g, 4.63 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.232 mmol Pd), Na2CO3 (0.90 g, 8.49 mmol), AcCN (10 mls), and H2O (10 mls) were combined and heated in the microwave at 150° C. for 10 minutes. The reaction was shown complete by TLC (CH2Cl2). The mixture was cooled, concentrated, slurried in CH2Cl2, filtered, and chromatographed over silica gel (CH2Cl2) to give 0.80 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 79%.