Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl.S(=O)(=O)(O)O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([N+:24]([O-:26])=[O:25])=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4methyl-2,6-dioxo-1-(2H)-pyrimidinyl]-benzoate in 30 ml of methylene chloride at room temperature is treated with stirring with 2.0 ml of 100% nitric acid. The solution is then treated with 5 drops of concentrated sulphuric acid and stirred for 48 hours at room temperature. The reaction mixture is poured into 150 ml of ice/water, diluted with 100 ml of ethyl acetate and washed four times with 150 ml of water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-5-nitro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 202°-205° C., is obtained.
Reaction SMILES: C1COCC1.CC1(C)[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:29](=[O:30])[C:28]4[C:27]5[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([CH3:34])([CH3:33])[C:18]=3[CH:35]=2)[CH2:9][O:8]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O>[OH:11][C@H:10]([CH2:9][OH:8])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:29](=[O:30])[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([CH3:34])([CH3:33])[C:18]=2[CH:35]=1
Reactant: CC1(C)OCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)c2cc(OC[C@H](O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 38 h
Yield: 106.3 %

Procedure:
To the solution of THF and water (4:1, 1 mL) of 8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A14-1, 30 mg, 0.07 mmol), camphor sulfonic acid (36 mg, 0.14 mmol) was added at room temperature. After stirring at room temperature for 38 hr, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 28 mg, 72%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with (S)-2-fluoro-2-methyl-malonic acid monoethyl ester in analogy to the description in example 73 to yield (S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid ethyl ester as colourless oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[CH2:28][CH2:27]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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].O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[C:29](=[O:33])[CH2:28][CH2:27]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCC4=O)n2n1
Temperature: 80 °C
Yield: 85.3 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (400 mg, 1.5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (770 mg, 3.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (240 mg, 0.30 mmol), potassium phosphate (1.0 g, 4.5 mmol), DME (6 mL) and H2O (2 mL) was heated in a sealed vessel at 80° C. for 12 h. The reaction was cooled to RT, then the organic layer was separated and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (SiO2) to afford 5-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-indan-1-one (410 mg, 85%) as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.07 (s, 1H), 7.78 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.17 (t, J=5.4 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 3.22-3.42 (m, 3H), 3.05-3.18 (m, 2H), 2.58-2.71 (m, 2H), 1.58-1.73 (m, 2H), 1.34-1.51 (m, 2H), 0.89-1.00 (m, 3H); LCMS (ESI) m/e 321.2 [(M+H)+, calcd for C19H21N4O 321.2].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH2:31]([O:33][C:34]1[N:39]=[CH:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][N:35]=1)[CH3:32].CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH2:31][CH3:32])=[N:39][CH:38]=3)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(OCC)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(CC4CCCCC4)c23)cn1
Temperature: 120 °C
Yield: 40 %

Procedure:
A mixture of 8-bromo-1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2-ethoxy-5-tributylstannanyl-pyrimidine (105 mg, 0.25 mmol) and PdCl2(PPh3)2 (24 mg, 0.034 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-35% EtOAc/hexanes+1% AcOH) to give 35 mg of the title compound. MS: (+) m/z 515.36 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:25]#[N:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:32]CC1>>[O:32]=[C:10]1[C:9]2[C:8]([C:25]#[N:26])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C
Yield: 73 %

Procedure:
A solution of 2-(piperidin-1-yl)-4-(thiophen-2-yl)-9H-fluorene-1-carbonitrile (356 mg) in THF was added sodium hydride (29 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; yield 73%; mp 226-228° C.; ESMS 371 (M++1); IR (KBr) 1710 cm−1 (CO), 2220 (CN).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=O)[CH:36]=[N:37][CH:38]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:39][C:35]4[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: O=Cc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3cncc(F)c3)nc2)c2cc(Cl)cnc21
Yield: 59.1 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (599, 80.0 mg, 0.20 mmol, prepared as described in Example 68, Scheme 185) in ethanol (2.0 mL) and acetic acid (0.10 mL, 0.0018 mol) were added 5-fluoro-pyridine-3-carbaldehyde (594, 62.7 mg, 0.50 mmol) and sodium cyanoborohydride on silica gel (1.200 mmol/g loading; 0.251 g, 0.30 mmol). The reaction was irradiated with microwave on 300 watts, 100° C. for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (601, 0.060 g, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]=[C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:25]=[O:26]>C1COCC1>[C:11]1(=[CH:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH:25]=[O:26])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C=C1CCCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C=C1CCCCCC1
Temperature: 25 °C
Yield: 72 %

Procedure:
4-bromo-2-cycloheptylidenemethylanisole (738 mg, 2.5 mmol) in THF (20 ml) was cooled to -78° C. while stirring under nitrogen. n-Butyllithium (1 ml, 2.5M in Hexane, 2.5 mmol) was added dropwise over 1 minute. N,N-Dimethylformamide (0.5 ml) was added rapidly. The ice bath was removed an the reaction was warmed to room temperature. The reaction was diluted with ethyl acetate (100 ml) and was washed with water (50 ml) and brine (50 ml). The organic solution was dried over MgSO4, filtered and concentrated. The product was purified via flash chromatography to yield 440 mg (1.8 mmol) of the title compound (72%).
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=1[F:19])[C:6]([O:8]CC)=O)C.Cl.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOCCOC.C(O)(=O)C.O>[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]1[N:30]=[C:4]([OH:20])[C:5]([C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[CH:15][C:16]=2[F:17])=[C:6]([OH:8])[N:29]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 120 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 2-(2,4,6-trifluoro-phenyl)-malonic acid diethyl ester (200 g, 0.67 mol), pyrazine-2-carboxamidine hydrochloride (132 g, 0.828 mol) and potassium carbonate (114 g, 0.828 mol) in 2-methyoxyethyl ether (diglyme, 600 mL) is heated to 120° C. and stirred for 4 h, then heated to 140° C. and stirred for an additional 2 h. The mixture is cooled to room temperature (25–30° C.) and water (1200 mL) is added over about 15 min. Acetic acid (50 g) is added over 15 min. and 82 ml of concentrated HCl is added over 15 min and the mixture is stirred for about 15 min. at room temperature at a pH of about 2–3. The solid is filtered and washed with water (2×400 mL) and isopropyl alcohol (IPA) (400 mL) and dried at 60° C./10 mmHg for 24 h to give a white solid 69% yield with 95% HPLC purity. 1H NMR (DMSO-d6): d 12.45 (bs, 2H), 9.41(s,1H), 8.91(s,1H), 8.46(m, 1H), 7.23(m, 2H).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3](OC)=[O:4].CC[O-].[Na+].[O:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[O:21][N:20]=2)[CH2:15]1>CO>[OH:4][C:3]1[CH2:2][CH:24]([C:22]2[O:21][N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][O:14][CH2:15]3)[CH:23]=2)[CH2:25][C:26](=[O:28])[CH:27]=1
Reactant: CC(=O)C=Cc1cc(C2CCOC2)no1
Reactant: COC(=O)CC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2cc(C3CCOC3)no2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.6 g of dimethyl malonate in 300 ml of methanol were initially taken, and 14.4 g of a 30% strength sodium ethylate solution in methanol were added at room temperature. Thereafter, 16.0 g of 4-[tetrahydrofur-3-ylisoxazol-5-yl]-3-buten-2-one were added and the mixture was stirred for 1 day at 25° C. The residue which remained after the solvent had been removed was taken up in 10% strength sodium hydroxide solution and stirred for 24 hours at 25° C. The sodium hydroxide phase was washed with methyl tert-butyl ether, acidified to pH 2 with concentrated hydrochloric acid and then heated at 85° C. for 2 hours. The solid formed was filtered off, washed with water and dried 12.3 g of a beige solid of melting point 142°-144° C. were obtained
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH3:15])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:16]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH3:19])=[O:17]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:19][O:18][C:16](=[O:17])/[CH:20]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH3:15]
Reactant: CCC/C(=C\C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-hexenal (6 g) was treated with (carbomethoxymethylene)triphenylphosphorane (11 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) for 4 days at room temperature. The ester was isolated in the normal manner to give 6.7 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:19])[F:20])=[CH:11][C:12]=2[S:13]([C:14]([F:16])([F:17])[F:15])=[O:27])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=S(c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (5.5 g, 5.9 mmol) in chloroform is cooled to 0° C., treated with 3-chloroperoxybenzoic acid (5.49 g, 60%, 19.1 mmol), stirred for several hours and filtered to remove solids. The solids are dissolved into ether and the organic solution is washed with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Recrystallization of the solid from ether gives the title product as a white solid (mp 98°-200° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=O)[CH3:36])[CH:30]=2)[CH3:28])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C.O.CO>[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:36])[CH:30]=2)[CH3:28])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(N(C)C(=O)C2CCN(C(C)=O)CC2)c1
Agent: CC(C)O[Ti+](OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N(C)c2cccc(C(C)Nc3ccccc3Oc3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)aniline (118 mg, 0.541 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-methylpiperidine-4-carboxamide (180 mg, 0.595 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (284 μL, 1.19 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (504 mg, 2.38 mmol, 4 eq.) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured into aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave (167 mg, 61%) as a white foam. 1H NMR (270 MHz, CDCl3) δ 1.2-1.38 (2H, m, CH2), 1.50 (3H, d, J=6.1 Hz, CH3), 1.55-1.80 (2H, m, CH2), 1.90 (3H, d, J=6.7 Hz CH3), 2.10-2.30 (2H, m, CH2), 2.39 and 2.65 (1H, m, CH2), 3.15 (3H, s, NCH3), 3.69 and 3.49 (1H, d, J=13.4 Hz, CH), 4.25-4.60 (3H, m, NH and CH), 6.30 (1H, d, J=8.0 Hz, Ar) 6.55 (1H, q, J=7.0 Hz, ArH), 6.75-6.95 (4H, m, ArH), 7.00-7.15 (2H, m, ArH), 7.23-7.51 (4H, m, ArH); LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.15 min; (ES+), m/z 506.4 HRMS (ESI) calcd. for C29H32ClN3O3 (M+H)+ 505.2132, found 506.2193. HPLC 100% purity.
Reaction SMILES: C[C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[OH-].[K+]>C(O)C>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH2:17][C:18]([OH:20])=[O:19])=[CH:2][C:14]=3[CH2:13]2)=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)Cc1c-2ccc(CC(=O)O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)Cc1cc(CC(=O)O)ccc1-2

Procedure:
A solution of 20mg. of methyl 7-methoxyfluorene-2-acetic acid in 7ml. of ethanol containing 0.5ml. of 50% aqueous potassium hydroxide solution is refluxed overnight. The mixture is acidified and the solid collected by filtration. Crystallization from chloroform-isopropyl ether gives 8mg. of the title compound, mp 200°-202°. The analytical sample is prepared by tube to tube evaporative distillation, mp 203-205°; λ KBr 5.93μ.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)#[CH:13]>>[F:20][C:16]1[CH:15]=[C:14]([C:12]#[C:13][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(F)c1
Product: Cc1cc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.2 (M++H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-3-fluoro-benzene.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.FC(F)(F)[C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:48].P([O-])([O-])([O-])=O.[OH-].[Na+].C([O:66][CH2:67][CH3:68])C>CCCCCC.CC(O)C>[OH:48][C@H:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:67](=[O:66])[CH3:68]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CCOCC
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(=O)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of 1-phenyl-1,2-propanedione, Compound 3, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH value of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (R)-1-hydroxy-1-phenyl-2-propanone, Compound 3a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CC(C)n1cc(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1cc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
59 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine-2-amine, 19 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 85° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 40 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 30 mg of the objective compound as brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([F:26])[N:3]=1.[OH-].[Na+]>O1CCOCC1>[F:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([F:1])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(F)nc(F)c2)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Fc1cc(-c2c[nH]c3ncccc23)cc(F)n1

Procedure:
A mixture of EXAMPLE 56A (8.01 g, 21.6 mmol) and 20% aqueous sodium hydroxide (12 mL, 21.6 mmol) in 1,4-dioxane (75 mL) was heated at 50° C. for 90 minutes. The mixture was concentrated and the residue triturated with water, filtered, and concentrated to give the title compound.