Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:7][C:8]2[S:9][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CN3CCCCC3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CCN(Cc2nc3c(s2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of tert-butyl 2-(piperidin-1-ylmethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.534 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) and reaction mixture was stirred at room temperature for 2 h. Solvent was evaporated under reduced pressure and residue was azeotroped twice with dichloromethane and used in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:7]>O1CCCC1.CCCCCC>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: c1cscn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Under a nitrogen atmosphere, 1.25 ml (17.62 mmol) of thiazole were dissolved in 20 ml of tetrahydrofuran at −70° C. 11.1 ml (17.62 mmol) [15% in n-hexane] were subsequently added dropwise at such a rate that the temperature did not exceed −67° C. The mixture was warmed to room temperature, then cooled to −70° C., and 3.76 g (17.62 mmol) of tert-butyl 3-formylpiperidine-1-carboxylate, dissolved in 5 ml of tetrahydrofuran, were added dropwise. The mixture was stirred at −70° C. for 1 h, warmed to room temperature and stirred for a further 2 h. Conventional work-up gave 5.18 g of tert-butyl 3-(hydroxythiazol-2-ylmethyl)-piperidine-1-carboxylate; HPLC/MS (M+H)+=299 as oil.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: NC1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 40 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2,2,2-trifluoroethylamine, to the title compound (46 mg, 40%) which was obtained as a white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:17]3[C:18]4[CH2:19][C@@H:20]([CH2:29][C:30]([OH:32])=O)[CH2:21][CH2:22][C:23]=4[S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:30]([CH2:29][C@@H:20]1[CH2:19][C:18]2[C:17]3[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:14][CH2:13]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][C:23]=2[CH2:22][CH2:21]1)(=[O:32])[NH2:37]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CC(=O)O)CC4)CC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of 2-[(12S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetic acid (148 mg, 0.32 mmol, 1.00 equiv) in 6 mL of distilled DMF was added NH4Cl (103 mg, 1.93 mmol, 6.00 equiv), EDCI (92 mg, 0.48 mmol, 1.50 equiv), 4-dimethylaminopyridine (58 mg, 0.47 mmol, 1.50 equiv) and HOBt (65 mg, 0.48 mmol, 1.50 equiv) successively and the resulting solution was stirred overnight at room temperature. The reaction was then quenched with water and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give 80 mg (54%) of the desired tert-butyl N-(4-[[(12S)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid. MS: m/z 460 (M+H)+.
Reaction SMILES: [C:1]12[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8][C:7]1[C:6](=[O:14])[NH:5][CH2:4][CH2:3][C:2]2=1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:5]2[C:6](=[O:14])[C:7]3[S:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:1]=4[C:2]=3[CH2:3][CH2:4]2)=[CH:22][C:23]([F:27])=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: O=C1NCCc2c1sc1ccccc21
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(sc3ccccc23)C1=O
Temperature: 100 °C
Yield: 32.8 %

Procedure:
A mixture of 329f (700 mg, 3.4 mmol), 197c (3.35 g, 10.2 mmol), XantPhos (200 mg, 0.34 mmol), Pd2(dba)3 (316 mg, 0.34 mmol) and Cs2CO3 (2.25 g, 6.8 mmol) in dioxane (50 mL) was heated at 100° C. for 15 h under argon atmosphere. It was then filtered and evaporated in vacuo. The residue was purified by column chromatography eluting with 1:3 ethyl acetate/petroleum ether to give 329g as a white solid (500 mg, 33%). MS: [M+H]+ 448.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.ClCCl.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1-c1ccc(F)cc1

Procedure:
5-Bromo-4′-fluoro-1,1′-biphenyl-2-ylamine was prepared from the above intermediate, 4-bromo-2-iodoaniline (12.6 g, 42.2 mmol), 4-fluorophenylboronic acid (5.9 g, 42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.69 g, 0.84 mmol), and a 5 N aqueous sodium hydroxide solution (85 mL, 425 mmol) according to the procedure and in the same manner as described in Example 32, Method A, Step a.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.FC1C=CC=CC=1[C:26]1[N:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>>[CH3:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([N:31]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:12])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Oc1ccc(-c2ccccc2F)nc1
Reactant: Cc1nc(-c2ccccc2)ncc1C=CC(=O)O
Product: Cc1nc(-c2ccccc2)ncc1CCC(=O)N1CCCCC1

Procedure:
The title compound was prepared from 3-(4-methyl-2-phenyl-pyrimidin-5-yl)-acrylic acid analogously as described in Example 15(b) and (c).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C([Sn](CCCC)(CCCC)[C:32]1[S:36][C:35]2=[C:37]([S:40][C:41]([F:44])([F:43])[F:42])[N:38]=[CH:39][N:34]2[CH:33]=1)CCC>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:32]3[S:36][C:35]4=[C:37]([S:40][C:41]([F:44])([F:43])[F:42])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC(F)(F)F)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SC(F)(F)F)c4s3)[C@H](C)[C@H]12
Yield: 14.8 %

Procedure:
The procedure of Example 1a) was repeated, except that 743 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.06 g 2-(tri-n-butylstannyl)-7-trifluoromethylthioimidazo[5,1-b]thiazole were used as the starting compounds. Thus, 172 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-trifluoromethylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-])=O.[Cl-].[NH4+]>[Zn].CC(C)=O.O>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[NH2:18]
Reactant: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1N
Reaction time: 4 h

Procedure:
To a solution of S-4-benzyl-2-nitrophenyl dimethylcarbamothioate (1.58 g, 4.99 mmol) in 25 mL 5:1 acetone/water under nitrogen was added zinc, nanosize activated powder (1.63 g, 25.0 mmol) and ammonium chloride (2.67 g, 49.9 mmol). The reaction became hot and was cooled with an ice bath. The heterogeneous reaction was allowed to stir for ˜4 h. The reaction was allowed to stand overnight and was partitioned between 200 mL EtOAc and water. The organic layer was washed with brine, and dried over sodium sulfate, filtered, and concentrated to give S-2-amino-4-benzylphenyl dimethylcarbamothioate which was used without further purification. MS (ESI) m/z: Calculated: 286.1; Observed: 287.0 (M++1).
Reaction SMILES: Cl[Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH2:5][CH3:6].C(=O)=O.Br[C:19]([F:22])([F:21])[F:20].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[CH2:3]([Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(F)Br
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCC[Si](CCCC)(CCCC)C(F)(F)F
Temperature: -78 °C
Yield: 67.1 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen sream, and charged with 5.0 g (20 mmol) of chlorotri-n-butylsilane and 10 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 6.2 mL (66 mmol) of bromotrifluoromethane (Freon 13B1) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cooling bath was removed and the mixture was allowed to warm to the temperature of the refluxing Freon (-59°C.). To this cold solution was added, dropwise, 8.0 mL (29 mmol) of hexaethylphosphorous triamide. The resulting solution was stirred at reflux for 1 hour. Removal of the condenser and continued stirring for 1 hour resulted in evaporation of excess Freon and warming of the solution to room temperature. Dilution with 30 mL of dichloromethane, water (three 30 mL portions) and 1N HCl (two 30 mL portions) washing, drying (MgSO4), and concentration afforded a residue which was short path distilled to give 3.6 g (64% yield) of tri-n-butyltrifluoromethylsilane: bp 53°-58° C. at 0.5 torr; 1H NMR (CDCl3) δ 0.60-1.10 (m, 5H), 1.10-1.56 (m, 4H); 19F NMR (CDCl3, relative to CFCl3) -61.6 ppm (s); IR (neat) 2956, 2925, 2872, 1214, 1058 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 199 (30, M-CF3), 143 (80), 105 (30), 101 (27), 87 (30), 77 (66), 63 (43), 59 (41), 55 (54), 47 (25), 43 (20), 41 (100). Anal. Calcd. for C13H27F3Si: C, 58.16; H, 10.14. Found: C, 58.26; H, 10.09.
Reaction SMILES: N1(C2C3C(=CC=CC=3)NC=2)CCOCC1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)[CH2:19][CH2:18]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCN(C)CC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc2c(N3CCOCC3)c[nH]c2c1
Product: CN1CCN(c2c[nH]c3ccccc23)CC1

Procedure:
Following a method similar to 3-morpholin-4-yl-1H-indole using 3-(4-Methyl-piperazin-1-yl)-1-triisopropylsilanyl-1H-indole (0.35 g, 0.94 mmol) and 1N solution of tetrabutylammonium fluoride (1.40 mL) to prepare the title compound. Purify by flash chromatography using 2 to 12% methanol in dichloromethane to give the title compound (0.12 g 60%). MS (ES) 216.1 (M+1)+.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[O:11][CH3:12])C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Cl-].[Na+].O>[OH:6][CH2:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[O:11][CH3:12]
Reactant: CCOC(C)OCc1ccccc1C(OC)c1cc(C)no1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(c1cc(C)no1)c1ccccc1CO
Yield: 99.9 %

Procedure:
To 3.05 g (10 mmol) of 5-[2-(1-ethoxyethyl)oxymethyl-α-methoxybenzyl]-3-methylisoxazole was added 0.25 g (1 mmol) of pyridinium p-toluenesulfonate and stirred under reflux for an hour. After completion of the reaction, 150 ml of brine was added and extracted twice with 80 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole (2.33 g, 99.9%) as colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-trifluoromethylphenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-(3-trifluoromethyl-phenyl)-piperidine-1-carboxylate as a light yellow oil; MS: 485 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[C:8]2[CH:9]=[C:10]3[CH:22]=[C:21]([F:23])[C:20](F)=[C:19]([F:25])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH2:17][F:18])[CH:15]=1)=[O:5])[CH3:2].[C:27]1([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[C:8]2[CH:9]=[C:10]3[CH:22]=[C:21]([F:23])[C:20]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:38]4)=[C:19]([F:25])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH2:17][F:18])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CCF)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1ccc(C2CNCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(CCF)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-1-(2-fluoroethyl)-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the following conditions: a suspension of 3-ethoxycarbonyl-1-(2-fluoroethyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g), (RS)-2-phenylpiperazine (1.7 g) and sodium carbonate (1.1 g) in dimethyl sulphoxide (40 cc) is heated with stirring to a temperature in the region of 100° C. for 2 hours. After cooling to approximately 20° C., the reaction mixture is poured into water (200 cc) and extracted with trichloromethane (3×100 cc). The combined organic extracts are washed with water (1×50 cc) and concentrated under reduced pressure (20 kPa) at a temperature in the region of 40° C. The oily residue is taken up with ethanol (100 cc) and concentrated again under reduced pressure under the above conditions. The solid obtained is recrystallized in ethanol (100 cc) containing dimethylformamide (20%), drained and washed with ethanol (2×20 cc). The expected product (2.4 g) is obtained in the form of a yellow solid, m.p. 208° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38].[CH3:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1B(O)O>>[CH2:46]([C:33]1[C:34]([NH:39][C@@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]([CH2:37][CH3:38])=[C:31]([C:50]2[CH:51]=[CH:52][C:53]([O:55][CH3:56])=[CH:54][C:49]=2[CH3:48])[N:32]=1)[CH3:47]
Reactant: CCc1nc(N[C@@H]2COC[C@H]2O)c(CC)nc1Br
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and 2-methyl-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3363, 1603, 1571, 1490, 1447, 1393, 1303, 1233, 1208, 1177, 1170, 1103, 1059, 887, 849 cm−1; OAMS supporting ions at: ESI+ 358.1; MS (EI) m/z 357 (M+); HRMS (FAB) calcd for C20H27N3O3+H1 358.2130, found 358.2142.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:38][CH:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:79][NH:80][CH2:81][CH2:82][OH:83].[OH-].[K+]>C1COCC1.CS(C)=O.C(O)(=O)C>[F:1][C:2]1[C:3]([NH:38][CH:39]2[CH2:40][CH2:41][CH:42]([OH:45])[CH2:43][CH2:44]2)=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([N:80]([CH2:81][CH2:82][OH:83])[CH3:79])=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)O)c3)cc12
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)N(C)CCO)c3)cc12
Reaction time: 15 h
Yield: 9 %

Procedure:
To a solution of 3-Fluoro-2-(4-hydroxy-cyclohexylamino)-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (63 mg, 0.1 mmol) in anhydrous THF (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (57 mg, 0.15 mmol), diisopropylethylamine (52 μL, 0.3 mmol), and 2-methylaminoethanol (11 mg, 0.15 mmol). The reaction solution was irradiated in a Personal Chemistry Optimizer at 100° C. for 2 min and 200 μL of 50% w/v aqueous potassium hydroxide was added. The mixture was stirred for 15 h and 100 μL of glacial acetic acid was added. The suspension was dissolved in DMSO and water and directly purified by reverse-phase HPLC to afford the title compound as a white powder (5 mg, 0.009 mmol, 9% yield). 1H-NMR (500 MHz, d6-DMSO, 70° C.) δ=8.48 (d, J=2 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.67 (s, 1H), 7.60 (dd, J=7 Hz, J2=2 Hz, 1H), 7.47 (dd, J1=14 Hz, J2=2.0 Hz, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 4.55 (m, 1H), 3.99 (m, 1H), 3.82 (s, 3H), 3.11 (m, 1H), 2.97 (s, 3H), 2.9 (m, 3H), 2.76 (m, 2H), 2.66 (m, 2H), 1.92 (m, 4H), 1.56 (m, 4H); MS: m/z 533 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([C:15]1[O:19][C:18]([CH2:20][CH2:21][CH3:22])=[N:17][C:16]=1[CH2:23][O:24]C1CCCCO1)[CH:8]([N+:31]([O-])=O)[CH2:7][CH2:6]2.Cl.C([O-])(O)=O.[Na+]>C(O)C.[Zn]>[NH2:31][C@@H:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[C:15]1[O:19][C:18]([CH2:20][CH2:21][CH3:22])=[N:17][C:16]=1[CH2:23][OH:24]
Reactant: CCCc1nc(COC2CCCCO2)c(C2c3cc(OC)c(OC)cc3CCC2[N+](=O)[O-])o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(CO)c([C@@H]2c3cc(OC)c(OC)cc3CC[C@H]2N)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of the compound from step 29d (1.16 g, 2.52 mmol) in 40 mL of ethanol was added 10 mL of 6 N HCl. The mixture was stirred for 30 min at room temperature, and zinc dust was added in portions until the yellow solution turned colorless. Satd. NaHCO3 solution was added until the mixture was at pH 8-9. The solid was removed by filtration and washed with methylene chloride. The flitrate and washings were combined, dried over MgSO4, concentrated, and purified by chromatography on silica gel, eluting with 5-40% methanol (containing 5%NH4OH) in methylene chloride, to afford 742 mg (85% yield) of the title product as a 1:6.5 mixture of cis:trans isomers. Recrystallization from 1:1 hexane:ethyl acetate provided the pure trans isomer as a solid. MS: 347(M+H)+. NMR (CDCl3) δ:6.62 (s, 1H), 6.29 (s, 1H), 4.62 and 4.52 (abq, J=13 Hz, 2H), 4.02 (d, J=10 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 3.17 (m, 1H), 3.03-2.79 (m, 2H), 2.65 (t, J=8 Hz, 2H), 2.18 (m, 1H), 1.81 (m, 1H), 1.72 (sx, J=8 Hz, 2H), 0.92 (t, J=8 Hz, 3H).