Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li+].CC([N-]C(C)C)C.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1>C1COCC1>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([C:31]3([OH:35])[CH2:34][CH2:33][CH2:32]3)([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1[C@@H]1C=CC(C(=O)OCc2ccccc2)C1
Reactant: O=C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a cold (−78 C), stirred solution of 6.17 g (20.9 mmol) of benzyl (4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0233) in 40 mL of dry THF, under Ar, was slowly added 23.3 mL of a commercial 1.8 M solution of LDA. The resulting solution was warmed to 0 C, stirreed at that temperature for 10 min, and then recooled to −78 C for the addition of 2.3 mL (31 mmol) of cyclobutanone. This solution was stirred at −78 C for 1 h, then quenched at −78 C by the slow addition of a solution of 4.0 mL of 12N HCl in 10 mL of THF. Ethyl acetate and excess 1 M citric acid were added and the mixture was allowed to warm to RT. Extractive workup was followed by flash chromatography on silica using 25% ethyl acetate in heptane to provide 5.55 g (73%) of the title compound as a thick amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44-1.56 (m, 1H) 1.88-2.31 (m, 6H) 2.12 (s, 6H) 2.27 (dd, J=14.7, 7.5 Hz, 1H) 2.76 (dd, J=14.5, 9.0 Hz, 1H) 5.18 (s, 2H) 5.26-5.32 (m, 1H) 5.71 (s, 2H) 6.06 (dd, 1H) 6.10 (dd, 1H) 7.30-7.39 (m, 5H). TLC Rf 0.36 (30% ethyl acetate in hexane). LC-MS ES+ 366.2.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([OH:8])[C@@H:3]1[OH:9]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2].C([O-])([O-])=O.[Ag+].[Ag+]>[O:8]=[C:4]1[C@H:3]([OH:9])[C@H:2]([CH3:1])[O:7][CH:6]=[CH:5]1
Reactant: C[C@@H]1OC=C[C@H](O)[C@@H]1O
Agent: [Ag+2]
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: C[C@@H]1OC=CC(=O)[C@@H]1O

Procedure:
In a 250 milliliter round-bottomed flask, 1 gram of L-fucal [Example 5 product] is dissolved in 100 milliliters of benzene. To this solution was added 20-25 grams of silver carbonate on celite (Fetizon's reagent), prepared as described below, and the mixture was stirred. The flask was equipped for simple distillation, and 20-25 milliliters of solvent was removed by distillation. During this time the yellow Fetizon's reagent becomes dark brown. The distillation assembly is replaced with an efficient reflux condenser and the mixture is refluxed for 1 hour, after which time the reaction is generally completed as judged by t.l.c. monitoring. The hot mixture is filtered through celite and the filtrate evaporated under reduced pressure to give 1,5-anhydro-3-oxo-2,3,6-trideoxy-L-threo-hex-1-enitol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccnc(CCl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-tert-butyl-2-hydroxymethylpyridine (0.36 g) in chloroform (10 ml) was added dropwise a solution of thionyl chloride (1 ml) in chloroform (5 ml) at room temperature and the mixture was stirred for 3 hours at ca. 50° C., After cooling to room temperature, the resultant mixture was concentrated in vacuo. The residue was taken up with chloroform and washed with saturated sodium carbonate aqueous solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-tert-butyl-2-chloromethylpyridine (0.37 g) as a brown oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6](=[O:9])[CH2:7][CH3:8].[BH4-].[Na+]>CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C@H:6]([OH:9])[CH2:7][CH3:8]
Reactant: CCC(=O)[C@H]1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](O)C1CCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R)-1-(tetrahydrofuran-2-yl)propan-1-one (16.16 g, 1 equiv) in MeOH was added portionwise sodium tetrahydroborate (4.77 g, 1 equiv). After stirring at 0° C. for 1 hour, the reaction was quenched with 5M HCl and allowed to stir for further for 10 minutes. The mixture was concentrated in vacuo to remove MeOH and EtOAc and water were added. The organic portion was separated and the aqueous layer extracted several times with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:9][C@H:10]1[CH2:14][C:13](=[O:15])[CH2:12][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1C[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(=O)C[C@@H]1OC(=O)c1ccccc1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate (205 mg, 0.716 mmol) prepared in Example 107b in dichloromethane (3.0 mL), a Dess-Martin reagent (610 mg, 1.44 mmol) was added, and the reaction solution was stirred for 2 hours. To the reaction solution, an aqueous sodium hydrogencarbonate solution (10 mL) was added, and an organic layer was extracted with dichloromethane (10 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=2:3) to yield the title compound (140 mg, 69%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:13][CH2:14][N:15](C(C)C)C(C)C.Cl.C(N)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:14]([NH:15][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:13]
Reactant: CC(C(=O)O)c1ccc(I)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)C(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.97 g (7.14 mmol) 2-(4-Iodo-phenyl)-propionic acid (111.1) and 1.25 mL (7.14 mmol) DIPEA are added to 582 mg (7.14 mmol) ethylamine hydrochloride in 70 mL DCM. 1.64 g (8.57 mmol) N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 194 mg (1.43 mmol) 1-hydroxy-7-azabenotriazole are added at 0° C. Subsequently, cooling is removed and the mixture is stirred for 20 h at rt. After that time, the mixture is washed with water and brine, dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; heptane:EtOAc 50:50).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (133 mg, 65.2%)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:21]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: BrC1C=CCCC1
Reactant: Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccccc1NC1C=CCCC1
Temperature: 75 °C
Yield: 70.4 %

Procedure:
To a solution of 2-bromoaniline (2.0 g, 12 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (2.4 g, 18 mmol) and 3-bromocyclohexene (2.7 mL, 23 mmol). The mixture was heated at 75° C. for 16 hours. The reaction was allowed to cool before being diluted with ethyl acetate (50 mL) and toluene (15 mL). The solution was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dried under high vacuum to yield 2.13 g (73%) of N-(2-bromophenyl)-N-cyclohex-2-en-1-ylamine. 1H NMR (DMSO-d6): δ 7.40 (d, 1H), 7.16 (t, 1H), 6.79 (d, 1H), 6.53 (t, 1H), 5.83-5.88 (m, 1H), 5.66-5.71 (m, 1H); 4.43 (d, 1H), 4.06 (m, 1H), 1.99 (m, 2H), 1.82 (m, 1H), 1.60 (m, 3H). MS m/z 252, 254 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]1([C:5]2[N:6]=[C:2]([N:19]3[CH2:20][CH2:21][CH:17]([C:15]([O:14][CH3:13])=[O:16])[CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1nc(-c2ccccc2)cs1
Reactant: COC(=O)C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Temperature: 80 °C
Yield: 20.8 %

Procedure:
A mixture of 2-bromo-4-phenylthiazole (300 mg, 1.25 mmol) and pyrrolidine-3-carboxylic acid methyl ester (177 mg, 1.37 mmol) and potassium phosphate (290 mg, 1.37 mmol) in dry toluene (5 mL) were taken in a sealed tube and purged argon gas for 10 min. A catalytic amount of tri-tert-butylphosphine (12 mg, 0.06 mmol) was added, followed by palladium acetate (15 mg, 0.06 mmol), and the reaction mixture was heated to 80° C. for 10 h. The reaction mixture was then filtered through Celite and the clear filtrate was concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica 60-120 mesh, eluant 15-18% EtOAc in petroleum ether) to get methyl 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylate (75 mg, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 7.44-7.31 (m, 4H), 3.88-3.78 (m, 2H), 3.75 (s, 3H), 3.70-3.67 (m, 1H), 3.61-3.55 (m, 1H), 3.32-3.23 (m, 1H), 2.41-2.32 (m, 2H). MS (ESI) m/z: Calculated for C16H16N2O2S: 288.09. found: 289.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][N:5]=[C:4]([C:18](O)=[O:19])[C:3]=1[CH3:21].COC(C1C(C)=C(Cl)C(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)=[CH:6][N:5]=[C:4]([C:18]([N:72]2[CH2:73][CH2:74][CH:69]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:70][CH2:71]2)=[O:19])[C:3]=1[CH3:21]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)ncc(-c2cccc(C(F)(F)F)c2)c1Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)c(Cl)c1C
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)ncc(-c2cccc(C(F)(F)F)c2)c1Cl

Procedure:
In analogy to the procedure described for example 1, 4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 3) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 452.1 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=[O:18])C.C(O)C>ClC1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:14])[CH2:16][C:17]([CH3:19])=[O:18])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: Clc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated in 50 ml of chlorobenzene together with 20 gm of acetoacetic acid ethyl ester, with the simultaneous distillation of ethanol, formed in the reaction. From the cold reaction mixture the precipitate was suctioned off, washed with dilute methanol and recrystallized from dilute acetic acid. The product had a melting point of 146°-147°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2=[N:7][C:8](=[S:10])[N:9]=[C:5]2[CH:4]=1.Cl[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[NH:7][C:8]([S:10][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[N+:24]([O-:26])=[O:25])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)=NC(=S)N=2
Reactant: COc1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
5,6-Dimethoxy benzimidazole-2-thione (4.0 g), 2-chloro-4-methoxy nitrobenzene (3.6 g) and potassium carbonate (2.65 g) were stirred together in dry dimethyl formamide (30 ml) at 95° for 3 days. The cooled mixture was poured onto water (300 ml) and the precipitate collected. The solid was washed with water and dried to leave the sub-title compound as a pale yellow solid, MS 361 bp 207.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 82.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:8].[N:22]1C=CC=C(C(O)C)[CH:23]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(N1CCNCC1)(OC(C)(C)C)=O>CS(C)=O.CCOC(C)=O.CO.C(Cl)Cl>[N:22]1[CH:5]=[CH:4][CH:3]=[C:2]([CH:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH3:8])[CH:23]=1
Reactant: CC(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(O)c1cccnc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(c1cccnc1)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This was prepared using the same procedure as for tert-butyl 4-(1-(pyridin-2-yl)ethyl)piperazine-1-carboxylate, but here using 1-(pyridin-3-yl)ethanol (J. Chem. Soc., Perkin Trans. 1, 2000, 4439-4444) (200 mg, 1.62 mmol), triethylamine (5.0 eq, 8.12 mmol, 1.13 mL), MsCl (2.0 eq, 3.25 mmol, 0.26 mL), CH2Cl2 (8 mL) at 0° C. for 30 minutes. A solution of ether-pentane (1:1, 20 mL) was added, the solid removed by filtration and the solvents removed in vacuo. The residue was then treated with N—BOC piperazine (4.0 eq, 6.50 mmol, 1.21 g) in DMSO (6 mL) at 60° C. for 18 h. Work up as described for tert-butyl 4-(1-(pyridin-2-yl)ethyl)piperazine-1-carboxylate, followed by column chromatography (EtOAc-MeOH, 95:5) gave the product (186 mg, 39% for two steps) as a colourless oil; 1H-NMR (500 MHz, CDCl3) 1.36 (d, J=6.8 Hz, 3H, CH3), 1.42 (s, 9H, C(CH3)3), 2.29-2.45 (m, 4H, piperazine N(CH2)2), 3.38 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.45 (q, J=6.8 Hz, 1H, CH), 7.23 (dd, br, J=7.9, 4.7 Hz, 1H, pyridine H-5), 7.64 (dt, J=7.8, 1.9 Hz, 1H, pyridine H-4), 8.47 (dd, J=4.8, 1.8 Hz, 1H, pyridine H-6), 8.52 (d, br, J=1.9 Hz, 1H, pyridine H-2);
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1COCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]([C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)[OH:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)on1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of 5-phenylisoxazole-3-carbaldehyde 38i (0.365 g, 2.1 mmol) in 15 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.5 mL, 2.74 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40i as a white solid. (48.8%). 1H NMR (CDCl3) δ 7.78-7.77 (m, 2H), 7.48-7.46 (m, 3H), 6.74 (s, 2H), 6.45 (s, 1H), 5.98 (d, 1H, J=3.5 Hz) 3.89 (s, 6H), 3.86 (s, 3H), 2.77 (d, 1H, J=3.5 Hz); MS (ESI) m/z 364.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[C:9]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH:8]=[C:7]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
A solution of (3,5-bis-trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (250 mg, 0.56 mmol), 4-chlorophenyl boronic acid (219 mg, 1.4 mmol), K2CO3 (2 M solution in H2O, 1.1 mL, 2.24 mmol) in DME (4.0 mL) and heated to 80° C. in the presence of bis(tri-t-butylphosphine) palladium (0) (cat) for 4 hrs. The mixture was cooled to room temperature filtered, diluted with EtOAc, washed with Na2CO3, dil HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give an off white solid. The residue was purified by flash column chromatography (EtOAc:petroleum ether), 1H NMR (CDCl3) δ 7.61 (t, 1H), 7.55 (d, 4H), 7.46 (d, 2H), 7.42 (d, 4H), 3.75 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[O:12][CH2:13][CH2:14][C@@:15]([CH:38]([F:40])[F:39])([C:17]3[CH:22]=[C:21]([N:23]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:20]=[CH:19][C:18]=3[F:37])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O1CCOCC1>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([F:37])=[C:17]([C@:15]2([CH:38]([F:39])[F:40])[CH2:14][CH2:13][O:12][C:11]([NH2:10])=[N:16]2)[CH:22]=1
Reactant: COc1ccc(C(NC2=N[C@@](c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCO1
Temperature: 23 °C
Reaction time: 60 h
Yield: 43.7 %

Procedure:
To a solution of (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(difluoromethyl)-4-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E8.1) (525 mg, 723 μmol) in dichloromethane (20 ml) was added at 23° C. trifluoroacetic acid (4.12 g, 2.79 ml, 36.2 mmol) and the mixture was stirred at 23° C. for 1 hour, whereupon 1 M HCl (14.5 ml, 14.5 mmol) and dioxane (40 ml) were added and the mixture was stirred vigorously at 23° C. for 60 hours. Poured into 1 M Na2CO3-solution, extracted with dichloromethane, washed the organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. The residue was purified by chromatography on 5 g silica gel with dichloromethane/methanol/ammonium hydroxide 110:10:1 to give (S)-4-(5-amino-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (82 mg, 316 μmol, 43.7% yield) as a light brown solid. MS (ISP): m/z=259.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]>[Pd].C(O)(=O)C>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:30])[CH2:15][CH2:16]2)=[CH:26][CH:25]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)c21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccc(N)cc4)CC3)c(F)c21

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(p-nitrobenzyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (6.0 g), acetic acid (150 ml), and 5% palladium on charcoal (1.0 g) was hydrogenated. The slurry was filtered and the filtrate concentrated to dryness. The residue was treated with water, neutralized with aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried and evaporated. The residue was chromatographed on silica gel. Elution with a mixture of chloroform and ethanol (20:1) and recrystallization from a mixture of chloroform and ethanol gave 7-[4-(p-aminobenzyl)-1-piperazinyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.