Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:10])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Br)c(N)n1
Reaction time: 4 h
Yield: 12.1 %

Procedure:
Under an argon atmosphere 6-amino-5-bromo-pyridin-2-ol (23 g, 122 mmol) was dissolved in DMF (300 mL). K2CO3 (50.6 g, 366 mmol) was added followed by the addition of methyl iodide (11.4 mL, 183 mmol). The mixture was stirred for 4 h while keeping the temperature at 20-25° C. The suspension was poured onto H2O (1 L) and the aqueous phase was extracted with EtOAc (×2). The combined organic phases washed with H2O (0.5 L) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluent toluene:heptane 2:1->100:0 followed by toluene:EtOAc 95:5 to afford 3-bromo-6-methoxy-pyridin-2-ylamine as a solid (3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=1[O:33][CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[OH:30])=[CH:27][C:26]=1[O:33][CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 25.0 g of 3-bromoquinoline is dissolved in 200 ml of dry ether and cooled to -60°. At this temperature there are added dropwise within 15 minutes 75.1 ml of a 1.6 molar solution of n-butyllithium, whereupon the mixture is stirred for 10 minutes. A solution of 26.5 g of vanillin benzyl ether in 250 ml of dry ether is added dropwise thereto at -60°, the mixture is subsequently stirred at room temperature for 3 hours, poured into about 1.5 l of ice-water and extracted three times with 600 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 1 kg of silica gel with methylene chloride/ethyl acetate (1:1). The crystalline crude product obtained is recrystallized from ethyl acetate. There is obtained α-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in the form of colourless crystals of m.p. 124°-125°.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:20]([OH:22])=O)=[N:10][C:11]([O:18][CH3:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[NH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[CH:25]([OH:30])[CH2:24][NH:23][C:20]([C:9]1[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[C:11]([O:18][CH3:19])[N:10]=1)=[O:22]
Reactant: NCC(O)C(F)(F)F
Reactant: COc1nc(C(=O)O)c(-n2c(C)ccc2C)cc1C(F)(F)F
Product: COc1nc(C(=O)NCC(O)C(F)(F)F)c(-n2c(C)ccc2C)cc1C(F)(F)F

Procedure:
This compound was prepared from 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D2) and 3-amino-1,1,1-trifluoropropan-2-ol analogously to Example 1; LC-MS Rt=1.50 mins [M+H]+ 426 (Method 2 minLC_v002).
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.Cl.C(#N)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Agent: Cl
Solvent: CC#N
Solvent: c1ccc2ncccc2c1
Product: CCC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (15.6 g) and copper powder (1 g) are suspended in quinoline (150 cc) and heated at 195°-200° C. for 20 minutes, and then at the boil for 10 minutes. After cooling, ice (300 g) and a 12 N concentrated aqueous solution of hydrogen chloride (100 cc) are added to the reaction mixture, which is extracted three times with methylene chloride (total 600 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), and then extracted twice with a 2 N aqueous solution of sodium hydroxide (total 400 cc) and three times with distilled water (total 600 cc). The combined aqueous alkaline phases are acidified to pH 1 by the addition of a 12 N concentrated aqueous solution of hydrogen chloride and extracted three times with methylene chloride (total 450 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (5 g), filtered and evaporated. The residue obtained (9.3 g) is dissolved in boiling acetonitrile (70 cc). After cooling, starting the crystallization and standing for one hour at 4° C., the resulting crystals are filtered off, washed once with iced acetonitrile (15 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (7.8 g), melting at 143° C., is thus obtained.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([CH2:11][C:12]([O:14][CH:15]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([OH:49])[CH:36]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([OH:32])[CH:19]=1)=[O:13])#[N:10].[CH3:50][C:51]([CH3:53])=O>>[C:9]([C:11](=[C:51]([CH3:53])[CH3:50])[C:12]([O:14][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:20]([OH:32])[CH:19]=1)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:37]([OH:49])[CH:36]=1)=[O:13])#[N:10]
Reactant: CC(C)=O
Reactant: N#CCC(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(C)=C(C#N)C(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 56 °C
Yield: 86 %

Procedure:
1 g of trifluoromethanesulfonic acid was added to a solution of 55.2 g (0.1 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl cyanoacetate in 300 ml of acetone, and the solution was heated for 3 hours at a temperature of 56° C. After cooling to room temperature, the resulting crystalline precipitate was filtered off with suction and recrystallized from acetone. After drying, 51 g (86 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl 2-cyano-3,3-dimethylacrylate were obtained in the form of colorless crystals having a melting point of 145° to 147° C. and a purity of 99 percent (HPLC). The structure of the compound obtained was confirmed by UV, IR and NMR spectra.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[O:20]
Reactant: COCCNCCOC
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)CBr
Temperature: -78 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a stirred solution of DCM, bis(2-methoxyethyl)amine (40.0 g, 44.0 mL, 300 mmol), and triethylamine (69.25 mL, 500 mmol), under a nitrogen atmosphere at −78° C. was added drop wise bromo acetyl bromide (34.8 mL, 400 mmol). After stirring at −78° C. for 5 h, the reaction mixture was allowed to warm up to −20° C. and then quenched by addition of water (60 mL). The organic phase was washed with distilled water (3×30 mL), saturated ammonium chloride (3×30 mL), saturated sodium bicarbonate (3×30 mL) and brine (2×30 mL). The organic phase was then dried over magnesium sulfate, filtered and solvents removed via rotary evaporation to yield a crude product in 82% yield (62.3 g, 245 mmol). The crude product was then distilled under high vacuum at 170° C. to give pale yellow crystals in 49% yield (35.57 g, 140 mmol). Pure product can also be recrystallised from the crude material with diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][OH:18])=[O:4].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[C:24]2N.C(N(CC)CC)C>C(O)C>[C:13]([NH:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:24]2[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:20]([F:32])([F:33])[F:19])[CH:22]=3)[N:27]=[CH:26][N:25]=2)[C@H:7]([CH2:17][OH:18])[CH2:8]1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1
Reactant: Nc1ncnc2ccc(C(F)(F)F)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)[C@H](CO)C1
Yield: 22.1 %

Procedure:
A solution of 2-amino-N-((1S,2R,4R)-4-(tert-butylamino)-2-(hydroxymethyl)cyclohexyl)acetamide (54 mg, 0.21 mmol), 6-(trifluoromethyl)quinazolin-4-amine (52 mg, 0.25 mmol), and triethylamine (25 mg, 0.25 mmol) in 3 mL of ethanol was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give 21 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[N:32]=[CH:31][C:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:35][CH:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.438 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.122 g, 15.2%). MS (APCI) Calc'd for M+1: 449.3. Found: 449.3. Anal. Calc'd for C25H32N6O2: C, 66.94; H, 7.19; N, 18.74. Found: C, 66.72; H, 7.13; N, 18.57.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[CH:21]=3)=[CH:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][N:6]=2)[CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 912454-38-7) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials; MS (ESI): 304.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1(F)CCCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Temperature: 130 °C
Yield: 55.5 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.1 g, 4.5 mmol), 3,3-difluoropiperidine hydrochloride (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and 3,3-difluoropiperidine hydrochloride (0.29 g, 1.8 mmol) were added and the mixture was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([OH:22])=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[ClH:32].[N:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:32].[CH2:1]([N:4]1[CH2:9][C:8]2[C:10]3[C:21]([O:22][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][C:19]([CH:23]([CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])=[CH:18][C:11]=3[O:12][C:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]=2[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: C=CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(C(C)C(C)CCCCC)cc1OC2(CC)CC

Procedure:
2-Allyl-5,5-diethyl-8-(3-methyl-2-octyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]-benzopyrano[3,4-d]-pyridine, γ-piperidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts to produce the desired product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH3:25])[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH3:25])[C:29](=[O:30])[CH:28]=[C:27]([CH3:32])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(C)=CC(=O)Cl
Reactant: CNc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Product: CC(C)=CC(=O)N(C)c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 110.4 %

Procedure:
Starting from {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amine (300 mg, 0.84 mmol) and 3,3 dimethyl acryloyl chloride (97 μL, 0.88 mmol) and following the procedure as outlined in Example 1, 403 mg of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-methyl-amide was isolated as a low melting solid in 100% purity @ 254 nm; LCMS (APCI): 435 [M+H]+.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Na].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])CCl>C(O)C.C(OCC)C>[CH3:13][C:14]1[CH:15]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200 ml of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1 g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid (yield 55%), having the characteristics of: m.p. 82° C.; NMR(CDCl3, 300 MHz) δ2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2CO), 6.93~7.70(m, 3H, ArH).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Clc1cnccn1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=286.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloropyrazine.
Reaction SMILES: Cl.C1(C[O:6][C:7]2[C:8]([O:27][CH3:28])=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[C:12]3[NH:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])CC1>CO>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:12]1[C:11]2[C:16](=[C:7]([OH:6])[C:8]([O:27][CH3:28])=[CH:9][CH:10]=2)[NH:15][C:14](=[O:17])[CH:13]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Temperature: 50 °C

Procedure:
Concentrated HCl (15 ml) was added to a solution of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (1.2 g, 2.90 mmol, Example 3) and methanol (8 ml). The reaction mixture was heated at 50° C. for 4 h and then concentrated. The residue was neutralized with sat'd NaHCO3, filtered (washed with ethanol and ether), and dried to give 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI): 352.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl>CCOCC.F[B-](F)(F)F.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[NH:11])[O:10][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(C(=N)OCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
To a refluxing solution of 2.72 g (12.9 mmol) of 2-(4-chlorophenyl)-3-methylbutyramide and 2.27 g (8.6 mmol) of 3-phenoxybenzyl bromide in a solution of 15 ml dichloromethane and 3 ml ethyl ether is added a solution of 1.83 g (9.5 mmol) of silver tetrafluoroborate in ether. The mixture is refluxed for 2 hours and then separated by pouring into ice cold aqueous ethyl acetate/sodium bicarbonate. The organic phase is washed with water, dried and stripped of solvent. The residue is triturated with ether and filtered. The filtrate is concentrated and chromatographed on silica gel, eluting with 25% ethyl acetate/-hexane, and then on plates using 35% ethyl acetate/hexane, to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 393 (M-hu +(M+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:29]=[N-:30]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 g, 2.54 mmol) was dissolved in TFA (15 mL) and the yellow solution was cooled in an ice bath. Sodium nitrite (0.351 g, 5.09 mmol) was added with stirring to give a dark yellow mixture. After 30 min, sodium azide (1.65 g, 25.4 mmol) was added followed immediately by Et2O (15 mL). The light yellow mixture was stirred in the ice bath for 30 min. It was partitioned between EtOAc and sufficient sat. aq. NaHCO3 solution to neutralize the acid. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 3-azido-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 gm, 2.3 mmole, 92% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.13 (2H, d, J=8.24 Hz), 7.82 (2H, d, J=4.58 Hz), 7.80 (1H, s), 5.24-5.30 (1H, m), 4.01 (3H, s), 1.38 (6H, d, J=6.10 Hz).
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27]>>[C:26]([NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=12)=[O:24])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 67 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 2-methylpropan-2-amine to yield the title compound as a white solid (23 mg, 67% yield). MS (apci) m/z=383.1 (M+H).