Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H:8]1[C@@H:12]([OH:13])[CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[C@@H:9]1[C:24]([OH:26])=[O:25])C1C=CC=CC=1.C(O)(=[O:29])C>[Pd]>[OH:29][C@H:8]1[C@H:12]([OH:13])[CH2:11][NH:10][C@@H:9]1[C:24]([OH:26])=[O:25]
Reactant: O=C(O)[C@@H]1[C@@H](Cc2ccccc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Product: O=C(O)[C@H]1NC[C@@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 93.5 %

Procedure:
(2S, 3R, 4R)-3-benzyl-N-benzyloxycarbonyl-4-hydroxyproline (17) (523 mg, 1.95 mmol) was dissolved in glacial acetic acid (12 ml) containing palladium black (100 mg) and stirred under hydrogen at atmospheric pressure for 48 hours. The solution was filtered and the solvent removed. Purification by flash chromatography (CMAW) and ion exchange resin gave (2S, 3R, 4R)-3,4-dihydroxyproline (220 mg, 93.5%) as a white crystalline solid, m.p. 220°-245° C. decomposed without melting (lit.37 250° dec.), [α]20D -12.2° (c, 0.83 in water) [lit.37 [α]D25 -19° (c, 0.4 in water)]; νmax (KBr disc) 3260, 1615 (CO), 1370, 1270, 1075, 1050 and 760 cm-1 ; 1H NMR δ (D2O) 3.35 (1H, d, H-5, J5,5' 12.5 Hz); 3.44 (1H, dd, H-5', J4,5' 3.7 Hz); 3.90 (1H, s, H-2); 4.14 (1H, dt, H-4, J3,4 1.2 Hz); 4.36 (1H, bs, H-3). 13C NMR (D2O) δ 51.71 (t, C-5); 66.33 (d, C-2); 74.75 (d, C-4); 79.14 (d, C-3); 171.86 (s, C-1). m/z: 124 (100%), 104 (77%), 148 (M+H+, 75%), 84 (67%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.NC1C=C2C(=CC=1)CC1(C3C(=NC=CC=3)NC1=O)C2>>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Product: O=Cc1ccc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21

Procedure:
Essentially following the procedures described for Intermediate 6, but using (±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 5) in place of (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound was obtained. MS: m/z=316 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>C1(C)C=CC=CC=1>[C:32]([O:31][C:30](=[O:36])[NH:29][C:25]1([C:22]2[CH:23]=[CH:24][C:19]([C:10]3[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[S:46])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:20][CH:21]=2)[CH2:28][CH2:27][CH2:26]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1C(=S)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
Tert-butyl (1-(4-(1-methyl-7-phenyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.412 mmol) was suspended in toluene (5 ml). Lawesson's reagent (125 mg, 0.309 mmol) was added at room temperature. The resulting mixture was heated under reflux for 5 hours. After it was cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in the minimum amount of dichloromethane (1 mL) and treated with diisopropyl ether (7 mL). A yellow solid crushed out. It was filtered and dried until constant weight (200 mg, 96%). LCMS (Method A): RT=7.08 min, M+1=502.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br.C(=O)([O-])O.[K+]>CO>[C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH:22][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=3[F:24])[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(F)cc1F

Procedure:
A solution of 7 ml of methanol containing 0.60 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide, 0.656 g of 2,4-difluorobenzyl bromide and 0.423 g of potassium hydrogencarbonate was stirred at 60° C. for 1 hour. The reaction solution was concentrated, and the residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to give 0.370 g of N-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide.
Reaction SMILES: [OH:1]O.[C:3]1([CH2:9][CH2:10][P:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([CH2:9][CH2:10][P:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:1])[OH:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OP(CCc1ccccc1)CCc1ccccc1
Reactant: OO
Solvent: CO
Product: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reaction time: 16 h
Yield: 30.6 %

Procedure:
Hydrogen peroxide (0.45 mL, 30%, 4.36 mmol) was added dropwise over 1 minute to crude bis(2-phenylethyl)phosphinous acid (1.12 g, 4.34 mmol) in methanol (6.5 mL). After 16 hours, the solvent was evaporated. The residue was basified with 1M NaOH and extracted twice with hexanes. The aqueous layer was acidified with 12M HCl, and the precipitate was filtered, rinsed with water, and dried in vacuo, affording crude product (628 mg) mp 70°-77° C., which was recrystallized from hot ethanol-water (50:50) to give bis(2-phenylethyl)phosphinic acid (364 mg) as a white solid, mp 84°-87° C. NMR δ2.02 (4H, m), 2.94 (4H, q), 6.8 (1H, br. s), 7.24 (10H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[NH2:13][C@@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([OH:21])[CH2:15]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[OH:21][C@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:14]([NH:13][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:15]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: N[C@@H]1CCCC[C@H](O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CCCC[C@H](O)C2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.4 g, 2.155 mmol) and (1S,3R)-3-aminocycloheptanol hydrochloride (0.428 g, 2.59 mmol; synthesis described herein) in DMF (3 mL) was added DIEA (1.126 mL, 6.46 mmol) and stirred at 60° C. for 1 h. LCMS shows the reaction to be completed. The reaction mixture was cooled to room temperature, and poured into water (50 mL). The suspension was stirred for five minutes, then filtered to afford 4-((1R,3S)-3-hydroxycycloheptylamino)-2-(methylthio)pyrimidine-5-carbonitrile (0.404 g, 1.451 mmol, 67.4% yield) as an off-white solid; 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.39 (s, 1H), 8.00 (d, J=7.4 Hz, 1H), 4.63 (d, J=3.9 Hz, 1H), 4.21 (br. s., 1H), 3.74 (td, J=8.5, 4.1 Hz, 1H), 2.47 (s, 3H), 1.66-1.97 (m, 5H), 1.35-1.66 ppm (m, 5H); MS (ESI) m/z 138.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]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+]>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].C1(C)C=CC=CC=1>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[CH2:23]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(-c2ccccn2)nc2c(C)ccc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(C)ccc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinoline (30 mg, 0.11 mmol) (described herein), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-6-yl)morpholine (29.3 mg, 0.13 mmol) (described herein), Pd2dba3 (9.58 mg, 10.5 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (9.98 mg, 0.021 mmol), sodium tert-butoxide (30.2 mg, 0.314 mmol), and toluene (1.0 mL) was stirred at 100° C. for 18 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Chromatography afforded 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3,8-dimethyl-2-(2-pyridin-yl)quinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69-8.76 (1H, m), 8.02-8.07 (1H, m), 7.92 (1H, td, J=7.7, 1.9 Hz), 7.50-7.56 (1H, m), 7.43-7.50 (1H, m), 7.34-7.43 (1H, m), 7.05 (1H, dd, J=12.2, 7.9 Hz), 5.70-5.75 (1H, m), 3.86 (1H, dt, J=8.9, 0.7 Hz), 3.68-3.79 (5H, m), 2.93-3.05 (4H, m), 2.79 (3H, s), 2.50 (3H, s), 1.56 (3H, s), 1.50 (3H, s). Mass Spectrum (ESI) m/e=484 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16](=O)[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]3[C:12]([CH3:15])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccc(F)cc1)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccc(F)cc1)C2
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.12 g) and aminoguanidine hydrochloride (59 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.046 ml), and the mixture was stirred at 90° C. for 1 hour and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol and isopropylether, and dried to give (E)-6-(4-fluorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 34) (0.12 g).
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.C(C1SC=CC=1)C.C(Cl)(=O)C.Cl.[OH-].[Na+].[CH2:20]([C:22]1[S:26][C:25]([C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1)[CH3:21].C([O-])(=O)C.[Na+].[Br:35]Br>CCCCCC.O>[Br:35][C:23]1[CH:24]=[C:25]([C:27](=[O:29])[CH3:28])[S:26][C:22]=1[CH2:20][CH3:21]
Reactant: BrBr
Reactant: CCc1ccc(C(C)=O)s1
Agent: CC(=O)[O-]
Agent: CCc1cccs1
Agent: Cl
Solvent: O
Solvent: CC(=O)Cl
Solvent: CCCCCC
Product: CCc1sc(C(C)=O)cc1Br
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Over a period of 20 min a solution of SnCl4 (60.9 g, 234 mmol) in hexane (20 mL) is added to a solution of 2-ethylthiophene (25 g, 223 mmol) and acetylchloride (18.4 g, 234 mmol) in hexane (80 mL). Evolving HCl gas is trapped in a NaOH solution. Evolution of HCl stops when about half of the SnCl4 solution is added. The black viscous mixture is warmed to 100° C. for 30 min, before it is cooled again to rt. The mixture is poured into ice/water (600 mL), extracted with diethyl ether (3×) and the combined etheral extracts are washed with NaOH (1M), sat. NaHCO3 solution and brine, dried over MgSO4, filtered and evaporated. The crude 1-(5-ethyl-thiophen-2-yl)-ethanone (35 g) is added to a solution of sodium acetate (16.0 g, 195 mmol) in water (160 mL) and the resulting emulsion is stirred vigorously. To this emulsion bromine (28.5 g, 178 mmol) is added dropwise over a period of 25 min. Upon complete addition of the bromine, sodium acetate (60 g, 731 mmol) is added and the pH of the mixture is adjusted to 9 by adding 10 M aq. NaOH solution. A further portion of bromine (12.4 g, 78 mmol) is added and stirring is continued for 15 min. The reaction is quenched by adding 1 M aq. Na2S2O3 solution and the mixture is extracted three times with diethyl ether. The organic extracts are washed with 1 N aq. NaOH, 2 N aq. HCl and brine, dried over MgSO4, filtered and evaporated to give 1-(4-bromo-5-ethyl-thiophen-2-yl)-ethanone (38 g) as a brown oil; LC-MS: tR=0.97 min, [M+1+CH3CN]+=274.20.
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(=O)c5ccccc5)CC4)ccc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 1.2 g of sodium hydrogen carbonate were added to 30 ml of water and the mixture was stirred at room temperature for 30 minutes. 5 ml of acetone having dissolved therein 1.0 g of benzoyl chloride was added dropwise to the mixture while ice-cooling followed by stirring at the same temperature as above for 30 minutes and then at room temperature for 1.5 hours to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus-treated from dimethylformamide gave 2.4 g of 8-(4-benzoyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[N:6]=1.[OH-].[Li+]>C1COCC1>[N:11]1([C:7]2[N:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:15]=[N:14][N:13]=[N:12]1
Reactant: COC(=O)Cc1cccc(-n2cnnn2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-n2cnnn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl[6-(1H-tetrazol-1-yl)pyridin-2-yl]acetate (367 mg, 1.67 mmol) in THF (5 mL) was added 1.5 mL of 1N aqueous lithium hydroxide solution. The reaction mixture was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in 4 mL of a 1N aqueous hydrochloric acid solution and extracted with DCM (3×20 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo to afford crude title compound which was used without further purification. LC/MS (M+H-28)+178.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([O:20]C)[CH:17]=[C:16]([Br:22])[C:15]=1O>>[Br:22][C:16]1[C:15]2[O:9][C:7]([C:6]3[CH:10]=[CH:11][C:3]([OH:2])=[CH:4][C:5]=3[CH3:12])=[N:13][C:14]=2[CH:19]=[C:18]([OH:20])[CH:17]=1
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1ccc(C(=O)O)c(C)c1
Product: Cc1cc(O)ccc1-c1nc2cc(O)cc(Br)c2o1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 21, from 4-methoxy-2-methylbenzoic acid, and 2-amino-6-bromo-4-methoxyphenol, and was obtained as a light purple solid, m.p. 120-135° C.; MS m/e 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
A mixture of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (222 g, 0.8 mol), 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (292 g, 0.96 mol) and cesium carbonate (312 g, 0.96 mol) in DMF (1.5 L) was heated at 65° C. for 28 hours. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (105 g, 0.34 mol) dissolved in DMF (150 mL) was added. The mixture was cooled to room temperature and poured into water (5 L) with stirring. The resulting taffy was separated from the supernatant and stirred with ethyl acetate (2.5 L) for 3 hours at room temperature. The resulting suspension was filtered and the filter cake was dried to yield methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate as a solid (245 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=9 Hz, 1H), 8.28 (d, J=1 Hz, 1H), 8.11 (m, 3H), 7.72 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (m, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.93 (s, 3H), 3.47 (m, 1H), 1.33 (d, J=7 Hz, 6H). ES-LCMS m/z 547 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1.[H-].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccc(F)cc1)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 100 mg (0.245 mmol) of methyl {4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate (preparation described in WO 2008/031513, example 9) were initially charged in tetrahydrofuran (10.0 ml) and the suspension was cooled to 0° C. Subsequently, 9.8 mg (0.245 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 30.5 μl (0.245 mmol) of 4-fluorobenzyl bromide were added dropwise and the reaction mixture was stirred at RT overnight. Subsequently, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed twice with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 91.8 mg (72% of theory) of the title compound in solid form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[C@H:10]([C:22]([F:25])([F:24])[F:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:22]([F:23])([F:24])[F:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C[C@H]1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN[C@H](C(F)(F)F)C1

Procedure:
The major diastereomer ([1-(R)-Phenylethyl]-(2S,4S)-2-(trifluoromethyl)piperidin-4-yl)carbamic acid tert-butyl ester, from step (d), is dissolved in ethanol and a catalytic amount of 10% Pd/C is added. The reaction is shaken under H2 (50 psi) on a Parr hydrogenator apparatus. After 6 hrs the mixture is filtered through celite® filter medium, and the filter pad is washed with ethanol. The filtrate is concentrated under vacuum to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([O:16][CH3:17])=[N:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:24]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>CCCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(OCC)(=O)C.C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([O:16][CH3:17])=[N:10][N:11]2[C:15]([Br:24])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nn2ccsc2c1NC(=O)OC(C)(C)C
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: COc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 66.9 %

Procedure:
To a mixture of tert-butyl(6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (16.5 g, 61.4 mmol) and THF (410 mL) was added n-butyllithium (2.77 M n-hexane solution: 62.1 mL, 172 mmol) while stirring at −78° C. After stirring the mixture at −78° C. for 40 minutes, 1,2-dibromotetrafluoroethane (10.2 mL, 86 mmol) was added, and the mixture was stirred for two hours while warming to mom temperature. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the mixture, and then acetic acid was added so that the mixture became weakly acidic. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/0 then 4/1) to obtain the title compound (14.3 g, 41.1 mmol).
Reaction SMILES: Cl.[C:2]([C:7]1[C:12]([NH:13]N)=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O>C(O)(=O)C>[CH2:5]([O:4][C:2]([C:7]1[CH:8]=[CH:9][CH2:10][C:11]2[C:12]=1[N:13]=[C:18]1[CH2:19][CH2:20][CH2:21][C:16]([CH3:23])([CH3:15])[C:17]=21)=[O:3])[CH3:6]
Reactant: CCOC(=O)c1ccccc1NN
Reactant: CC1(C)CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C2N=C3CCCC(C)(C)C3=C2CC=C1
Yield: 58.1 %

Procedure:
Using the procedure of Example 1, the reaction of 29.0 g of 6-carbethoxyphenylhydrazine hydrochloride with 16.9 g of 2,2-dimethylcyclohexanone in 250 ml of 80% aqueous acetic acid afforded 21.1 g (58%) of 1,2,3,4-tetrahydro-1,1-dimethyl-9H-dibenzo [b,d]pyrrole-6-carboxylic acid ethyl ester as an orange solid after chromatographic purification.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[C:17](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:18]>>[Br:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[NH:1][C:17](=[O:18])[N:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)NCC(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1CC(F)(F)F
Yield: 266.5 %

Procedure:
8-Bromo-3-(2,2,2-trifluoroethyl)quinazoline-2,4(1H,3H)-dione (501b, 1.53 g, 88%) was prepared according to the procedures described for 720 using 2-amino-3-bromo-N-(2,2,2-trifluoroethyl)benzamide (1.6 g, 5.39 mmol, 501a) and tri-phosgene (0.5 g, 1.777 mmol, Sigma Aldrich) as the reagents. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (1H, s) 8.01 (2H, d, J=7.82 Hz) 7.20 (1H, t, J=7.82 Hz) 4.73 (2H, q, J=9.19 Hz). m/z (ESI, +ve) 322.9/324.9 (M+H)+.