Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1C(=O)C[S:8][C:7]1([CH3:13])[CH3:12].I[CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26]1[CH2:30][O:29]C[CH2:27]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:30](=[O:29])[C:26]([CH3:27])([CH3:15])[S:8][C:7]1([CH3:12])[CH3:13]
Reactant: CC1(C)SCC(=O)N1CCCCBr
Reactant: C1CCOC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC1(C)SC(C)(C)N(CCCCBr)C1=O
Temperature: -75 °C
Reaction time: 0.42 h

Procedure:
To a -75° C. solution of 3-(4-bromobutyl)-2,2-dimethyl-4-thiazolidinone (13.18 g), iodomethane (22.83 g) and THF (30 ml) was added a -75° C. solution of lithium bis(trimethylsilyl)amide (0.100 mol) in THF (110 ml) over a period of 12 minutes. The resulting solution was stirred at -75° C. for 25 minutes, removed from the cold bath and acidified with 1N HCl (250 ml). The aqueous mixture was extracted with diethylether (3×125 ml). The combined extracts were washed with brine (150 ml), dried (anhydrous Na2SO4) and concentrated under reduced pressure to give 16.86 g of liquid. Column chromatography of the liquid using silica gel (about 600 g) and elution with 30% ethyl acetate/hexanes afforded 12.50 g of oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.CN(C(ON1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN([CH:62]=[O:63])C>>[F:25][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:62](=[O:63])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:40]=2)=[CH:7][C:6]=1[C@@:8]12[O:16][CH2:15][CH2:14][C@@H:13]1[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]2
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ccccn4)ccc3F)OCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A mixture of tert-butyl ((4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (step G of Preparation 1, 15 mg, 0.041 mmol), HATU (23.28 mg, 0.061 mmol), and DIEA (14.26 μL, 0.082 mmol) in DMF (136 μL) was stirred at rt for 2 h, and the crude product was purified by prep HPLC (NH4OAc conditions, see Preparation 3) eluting with 0-100% B over 12 min to give tert-butyl ((4aS,7aS)-7a-(2-fluoro-5-(picolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (12 mg, 0.025 mmol, 62.2% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 10.08 (s, 1H), 8.66 (d, J=4.6 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 8.06 (dt, J=8.4, 3.6 Hz, 1H), 7.94 (td, J=7.7, 1.7 Hz, 1H), 7.70 (d, J=4.3 Hz, 1H), 7.53 (ddd, J=7.5, 4.8, 1.0 Hz, 1H), 7.13 (dd, J=10.8, 9.0 Hz, 1H), 4.23-4.11 (m, 2H), 3.30 (d, J=12.4 Hz, 1H), 3.00 (br. s., 1H), 2.92-2.86 (m, 1H), 2.39 (dd, J=12.6, 7.4 Hz, 1H), 2.26-2.15 (m, 1H), 2.10 (s, 4H), 2.03 (s, 1H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc(C)c2c(c1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2c(C)cc(C)cc2C1
Yield: 95.6 %

Procedure:
20.4 g (117 mmol) of 2,5,7-trimethyl-1-indanone (1) were dissolved in 300 ml of a mixture of tetrahydrofuran/methanol (2:1), and 6.6 g (175 mmol) of NaBH4 were added at room temperature. The mixture was stirred for a further hour, 50 ml of half-concentrated HCl were added and the mixture was extracted with ether. The combined organic phases were dried over sodium sulfate and freed from the solvent. The residue was transferred to a distillation apparatus, and 13 g of magnesium sulfate were added. A vacuum of about 10 mbar was applied and the mixture was heated up until the product distilled over (130-150° C.). Distillation gave 17.7 g of the indene 2 as a colorless oil. The yield was 96%.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10]C)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:13][S:14][CH2:15][C:16](=[O:35])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:31][C:32](=[O:34])[CH3:33])[CH2:27][O:28][CH2:29][CH3:30])=[CH:20][CH:19]=1>CCOCC>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:32]([O:31][CH:26]([CH2:27][O:28][CH2:29][CH3:30])[CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([CH2:15][S+:14]([CH3:1])[CH3:13])=[O:35])=[CH:23][CH:22]=1)(=[O:34])[CH3:33]
Reactant: CCOCC(COc1ccc(NC(=O)CSC)cc1)OC(C)=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CCOCC(COc1ccc(NC(=O)C[S+](C)C)cc1)OC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A 7 g quantity of methyl p-toluenesulfonate was added to 3.41 g of 4-(2-acetoxy-3-ethoxypropoxy)phenylcarbamoylmethyl methyl sulfide. The mixture was stirred at room temperature for 8 hours. Ether was added to the reaction mixture and the insoluble solid was filtered off, and recrystallized from ethanol-ether, giving 5.10 g of 4-(2-acetoxy-3-ethoxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (Compound 2) in 96.6% yield, M.P. 100° to 105° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(=O)(O)[O-].[Na+]>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(CNCCCCCCOCCCCOc2ccc3ccccc3c2)cc1
Yield: 95.6 %

Procedure:
2-[4-[(6-Bromohexyl)oxy]butoxy]naphthalene (2.25 g) and benzylamine (3.88 g) were stirred under nitrogen at ca. 125° for 2 h. The solution was diluted with 8% sodium bicarbonate (100 ml) and extracted with diethyl ether (2×100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (98:2:1) gave the title compound as a yellow oil (2.3 g), t.l.c. (System C 40:10:1) Rf 0.71.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:22](=[O:24])[CH3:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 56 b), the acylation of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester [Example 56 a)] with acetic acid anhydride yielded the title compound as a white solid; MS: m/e=334 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(CC)CC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 5 mmol), 2-chloro-N,N-diethylacetamide (1 mL, 7.5 mmol) and cesium carbonate (5 g, 15 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (160 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.52 g of 5-diethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 40.2 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-5-chloropyridine (129 mg; 1.00 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (eluent: 25% ethyl acetate/hexanes) 160 mg of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-5-chloro-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C22H24N3O2ClNa(M++Na+) 420.1449, found 420.1451.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:15]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1=[O:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1COCCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1COCCN1C(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 100 ml, three neck round bottom flask is equipped with a stir bar, a condenser, an addition funnel, a thermometer, and a temperature control device (Therm-O-Watch™, I2R). To this reaction flask is added the 3-oxomorpholine synthesized above (5.5 g, 0.054 moles), triethylamine (Aldrich, 6.0 g, 0.059 moles), and toluene (Baker, 15.0 g). To the addition funnel is added benzoyl chloride (Aldrich, 7.6 g, 0.054 moles). The reaction is heated to 90° C. under argon, and the benzoyl chloride is charged dropwise into the flask. After the addition is complete, the reaction is heated under reflux for 10 hours under argon as a white precipitate forms. The reaction mixture is then cooled and the precipitate is removed by vacuum filtration. Solvent is stripped from the resulting filtrate on a Kugelrohr apparatus at 2 mmHg and 70° C. for 1 hour to obtain the desired N-benzoyl-3-oxomorpholine as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([Cl:13])[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[ClH:13].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[CH:5]([C:16]([OH:18])=[O:17])[CH2:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CCN1CC(C(=O)O)C(=O)c2cc(Br)c(N3CCNCC3)cc21
Product: Cl
Yield: 67 %

Procedure:
A mixture of 1-ethyl-6-bromo-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.65 g, piperazine 2.15 g and pyridine 2 ml was refluxed for 12 hours by heating. The reaction mixture was evaporated under vacuum and dissolved in aqueous acetic acid. The insoluble matters were removed by filtration. The filtrate was neutralized with an aqueous solution of NaOH. The precipitated crystals were collected by filtration and washed with water. The precipitate was recrystallized from a mixed solvent of concentrated hydrochloric acid and ethanol to obtain 1.4 g (67%) of 1-ethyl-6-bromo-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride as colorless needles.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:27][CH2:28]Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([O:14][CH3:15])=[O:13])[CH2:28][CH2:27]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: ClCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mL (1.0 m, 2 Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of 1-bromo-2-chloroethane in 100 mL dry THF were reacted as described in Preparation 11, except that the reaction mixture was stirred for one hour at ambient temperature before work-up. This reaction yielded 4.21 g of a brown oil. This material was purified via silica gel chromatography eluting with a gradient solvent of hexane to hexane/EtOAc 19:1 to yield the title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C. Calculated for C—15H20O2:
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]=[C:29]=[O:30])=[C:18]([F:31])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([F:31])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: Cc1nnc(-c2cc(N=C=O)c(F)cc2Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.04 g of sodium hydride (oil, purity: 55%) in 75 ml of dimethylformamide, a solution of 4.3 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 58 ml of toluene was added dropwise of 0° C. over a period of 15 minutes. Thereafter, the solution was stirred at 0° C. for 15 minutes and then cooled to -30° C., followed by dropwise addition of a solution of 5.7 g of 4-chloro -2-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl isocyanate in 60 ml of toluene. The resulting mixed solution was stirred at room temperature for 3 hours.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11](Br)[CH:10]=[C:9]([Br:14])[CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.CN(C)[CH:26]=[O:27]>CCCCCC.C(OCC)C.O>[Br:14][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[OH:21])[CH:8]=1)[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: O=Cc1cc(Br)cc(C(O)c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (22.0 ml) was added dropwise to a stirred suspension of 1,3,5-tribromobenzene (15.74 g) in dry diethyl ether (500 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and then 4-fluorobenzaldehyde (6.83 g) was added dropwise. Stirring at -78° C. was continued for a further 30 minutes and then another equivalent of n-butyllithium (22.0 ml of 2.5M solution in hexane) was added dropwise. The mixture was stirred at -78° C. for another 15 minutes and then N,N-dimethylformamide (15.45 g) was added. Stirring was continued for 1 hour and then water (200 ml) was added. The mixture was allowed to reach room temperature and the organic layer was separated and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane gave impurity, and further elution with dichloromethane/methanol (99:1) gave the title compound as a gum (10.94 g), Rf 0.2 (SS 3). Found: C,53.99; H,3.41. C14H10BrFO2 requires C,54.39; H,3.26%
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=O.[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:24]([N:11]1[C:12]2[C:7](=[C:6]([OH:38])[C:5]([C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=2)[CH:8]=[C:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:10]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCC(=O)O
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 1-benzyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.11 mmol), β-alanine (818 mg, 9.13 mmol) and NaOMe solution (13.7 mL, 6.85 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 38 mg of the title compound as a light yellow solid. MS: (+) m/z 566.38 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)Cl.[OH-].[Na+]>CO.O>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: Nc1ccnc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)NC(=O)C1CCN(Cc2nccc(N)n2)CC1
Yield: 94 %

Procedure:
A solution of 2-chloromethyl-pyrimidin-4-ylamine (Imperial Chemical Industries PLC Patent: U.S. Pat. No. 4,447,441 A1, 1984; 300 mg, 2.1 mmol) in methanol (25 mL) is treated with piperidine-4-carboxylic acid tert-butylamide (404 mg, 2.19 mmol) and TEA (0.872 mL, 6.27 mmol). The resulting mixture is heated at reflux overnight. DCM (25 mL) and water (25 mL) are added followed by NaOH 1M to adjust at pH 10. The organic phase is separated. The aqueous phase is extracted with DCM (25 mL). The combined organic phases are dried over MgSO4, filtered and evaporated. Evaporation of the solvent yields the crude product (0.57 g, 94%) as a brownish solid; LC-MS A: tR=0.40 min; [M+H]+=292.14.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), glycine ethyl ester hydrochloride (135 mg) and triethylamine (450 mg) were added to pyridine (1,000 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 4 times repeatedly. Ethanol (1 ml) and distilled water (1 ml) were added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain an about 1:1 mixture (106 mg) of the title compound and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the raw material, as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=1.CC(OC(C)=O)=O.C([O-])(=O)C.[K+].[N:29](OC(C)(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:12][N:29]=[CH:13]2
Reactant: Cc1cc(Oc2cccc(Cl)c2)ccc1N
Reactant: CC(C)(C)ON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
4-(3-Chloro-phenoxy)-2-methyl-phenylamine (0.87 g, 3.74 mmol) was dissolved in chloroform. Ac2O (0.878 g, 8.61 mmol) was then added dropwise over 10 min at 0° C. and the mixture was stirred for 1 h at 25° C. Potassium acetate (110 mg, 1.12 mmol) and t-butyl nitrite (829 mg, 8.05 mmol) were added to the reaction mixture and the mixture was heated at 80° C. for 16 h. This mixture was then concentrated, conc. HBr was added and the mixture was stirred for 16 h at 25° C. The pH of the mixture was adjusted to pH 7 using KOH solution and the resulting mixture was extracted with EtOAc (3×50 mL). The organic phase was washed with brine (3×10 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (11% EtOAc in hexanes) to afford 5-(3-chloro-phenoxy)-1H-indazole (152 mg, 17%). MS (M+H)+=245; 1H NMR (CDCl3) δ: 8.03 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (br.s., 1H), 7.21 (d, J=6.18 Hz, 1H), 7.16 (dd, J=6.5, 1.1 Hz, 1H); 7.08 (d, J=5.8 Hz, 1H), 6.93 (br.s., 1H), 6.86 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)O)[CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH2:8][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1C(O)c1ccc(-c2ccccn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of the above 5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol (1.59 g) in trifluoroacetic acid (40 ml) was cooled to 0° C., and thereto were added gradually sodium triacetoxyborohydride (4.68 g). The mixture was stirred at room temperature for one hour, and cooled again to 0° C. 10% aqueous sodium hydroxide solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired 5-bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (1.38 g) as a colorless solid. APCI-Mass m/Z 344/346 (M+H).